
==== Front
Adv Hematol
Adv Hematol
ah
Advances in Hematology
1687-9104
1687-9112
Hindawi

10.1155/2024/1370364
Review Article
The Role of Methylation in Chronic Lymphocytic Leukemia and Its Prognostic and Therapeutic Impacts in the Disease: A Systematic Review
https://orcid.org/0000-0002-6508-5805
Chatzidavid Sevastianos sebastianx87@yahoo.com
1 2
https://orcid.org/0000-0003-4721-0809
Kontandreopoulou Christina-Nefeli 1
https://orcid.org/0000-0003-2938-280X
Giannakopoulou Nefeli 3
https://orcid.org/0000-0003-2692-5944
Diamantopoulos Panagiotis T. 1
https://orcid.org/0000-0003-3918-4401
Stafylidis Christos 1
https://orcid.org/0000-0001-9805-9112
Kyrtsonis Marie-Christine 4
https://orcid.org/0000-0001-8197-9895
Dimou Maria 4
https://orcid.org/0000-0003-0387-3993
Panayiotidis Panayiotis 5
https://orcid.org/0000-0002-2287-4150
Viniou Nora-Athina 1 6
1Hematology Unit, First Department of Internal Medicine, Laikon General Hospital, National and Kapodistrian University of Athens, Athens, Greece
2Thalassemia and Sickle Cell Disease Center, Laikon General Hospital, Athens, Greece
3Second Department of Hematology, Iaso General Hospital, Athens, Greece
4Hematology Section of the First Department of Propaedeutic Internal Medicine, Laikon University Hospital, Athens, Greece
5Department of Hematology and Bone Marrow Transplantation Unit, National and Kapodistrian University of Athens, School of Medicine, Laikon General Hospital, Athens, Greece
6Hematology Department, Iatriko Kentro Palaiou Falirou, Athens, Greece
Academic Editor: Manishekhar Kumar

2024
23 2 2024
2024 137036422 12 2023
4 2 2024
9 2 2024
Copyright © 2024 Sevastianos Chatzidavid et al.
2024
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Epigenetic regulation has been thoroughly investigated in recent years and has emerged as an important aspect of chronic lymphocytic leukemia (CLL) biology. Characteristic aberrant features such as methylation patterns and global DNA hypomethylation were the early findings of the research during the last decades. The investigation in this field led to the identification of a large number of genes where methylation features correlated with important clinical and laboratory parameters. Gene-specific analyses investigated methylation in the gene body enhancer regions as well as promoter regions. The findings included genes and proteins involved in key pathways that play central roles in the pathophysiology of the disease. Τhe application of these findings beyond the theoretical understanding can not only lead to the creation of prognostic and predictive models and scores but also to the design of novel therapeutic agents. The following is a review focusing on the present knowledge about single gene/gene promoter methylation or mRNA expression in CLL cases as well as records of older data that have been published in past papers.
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pmc1. Introduction

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of clonal B cells in peripheral blood, bone marrow, and secondary lymphoid organs. It is the most common leukemia in adults of Western countries and accounts for approximately 2–35 percent of all leukemias in the United States [1]. CLL is more common in men with a male to female ratio ranging from 1.2 : 1 to 1.8 : 1 [1, 2] and is considered to be a disease of the elderly as the median age at diagnosis is 70 years and an incidence increasing rapidly with increasing age [3]. Despite characterized by a common morphology and immunophenotype pattern, CLL shows a variable clinical behavior spectrum. At one end, some CLL patients have a very indolent disease course and may not require treatment for many years, while at the other end, some patients present a very aggressive disease early from diagnosis and require prompt treatment with lower survival rates despite therapy [4].

In terms of genetic pathobiology, at least one of the four common chromosomal abnormalities (deletion 13q14, trisomy 12, deletion 11q22-23, and deletion 17p12) can be detected by interphase fluorescence in situ hybridization in most patients [5]. Most CLL tumors have myriads of somatic gene mutations. Of these, tumor protein 53 (TP53), ataxia telangiectasia mutated (ATM), neurogenic locus, notch homolog protein (NOTCH), and subunit 1 of the splicing factor 3b protein complex (SF3B1) genes are the most frequently mutated at diagnosis [6, 7]. Several other gene mutations seen in CLL tumors are involved in important cellular signaling pathways. NOTCH signaling, B-cell receptor (BCR) signaling, Toll-like receptor, mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK-Erk) pathway, nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) signaling, chromatin modifiers signaling, cell cycle signaling, DNA damage signaling, and RNA splicing are some of the many pathways investigated [6–10]. Moreover, it is well documented that the interaction between CLL tumor cells and antigens is regulated by the somatic hypermutation load of the immunoglobulin heavy chain variable region genes [11].

In the complex domain of the tumor microenvironment, CLL cells seem to influence the kind and arrangement of the cells surrounding them, and they are highly dependent on signals from these cells for their own survival and proliferation, encouraging a leukemia-supportive and immunosuppressive microenvironment [11].

Methylation of DNA is an enzyme-mediated modification of DNA structure without interfering in the specific sequence of the base pairs for the gene encoded. Although DNA methylation is important in normal biologic processes, aberrant patterns of methylation are observed in several malignancies. Specifically, two patterns have been mainly described, namely, large sites of global hypomethylation along the genome and localized areas of hypermethylation at CpG islands, within the gene promoter regions. Ιn more and more studies in neoplastic diseases in recent years, there has been an emergence of evidence that methylation of the promoter regions of hundreds of genes, including tumor suppressor genes, results in the failure to express their normal purpose. In other cases, DNA methylation may represent an early step in the pathway by which normal tissue cells undergo tumorigenesis. Some other possible mechanisms for mutational induction secondary to DNA methylation include failure to produce DNA repair proteins that normally protect from mutations and predisposition to increased oxidative DNA damage, resulting in increased mutation potential [12].

Abnormal DNA methylation has been documented in many solid neoplasms, including breast cancer, lung, prostate, colorectal cancer, and melanoma. As described above, hypermethylation of promoter regions inhibits the expression of tumor suppressor genes while hypomethylation activates an oncogene expression. Global hypomethylation is also of crucial role, leading to genomic and chromosomal instability. For instance, BRCA1/2 genes are two of the most studied genes in breast cancer. The hypermethylation of their promoter regions is reported to result in their inactivation and consequent increased risk of breast cancer [13].

As regards CLL, a global DNA methylation pattern was reported to be relatively stable during the disease course and similar both in resting and proliferative cell compartments, implying that aberrant methylation may present as an early leukemogenic event with early indications of specific gene epigenetic changes in CLL samples being described over 30 years ago [14]. Global DNA hypomethylation was reported few years later [15].

Except CLL, abnormal function of basic methylation‐related enzymes is widely reported in several hematological malignancies, such as in myelodysplastic syndromes, myeloproliferative neoplasms, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, and diffuse large B‐cell lymphoma. The final DNA methylation patterns are suggested to be frequently lineage specific and accompanied by specific secondary mutations [16].

The research in this field led to the study and discovery of a large number of genes whose methylation plays an important role in their regulation, while certain correlations with clinical and laboratory parameters were also identified. The streptothricin acetyltransferase, alpha (SAT-α) gene, whose methylation levels were found to be an independent marker of poor treatment-free survival was an early example [17].

With the appearance and application of newer technics such as whole-genome bisulfite sequencing and DNA methylation arrays, global DNA hypomethylation was confirmed and it was reported that gene body and enhancer regions rather than promoter regions were primarily involved [18, 19] whereas hypermethylation was described to occur mainly in transcribed genomic regions [20] and regions affecting other regulatory mechanisms such as spliceosome [21]. After the CLL genome was discovered to be globally hypomethylated, research for aberrantly methylated oncogene targets revealed that hypomethylation of the B cell lymphoma 2 (BCL2) gene, an important antiapoptotic gene, correlated with higher protein expression in CLL [22]. In the following studies, multiple drug-resistance protein 1 (MDR1) and T-cell leukemia/lymphoma 1 (TCL1) genes were reported to be both hypomethylated and upregulated in CLL [23, 24]. Moreover, the nuclear factor of activated T-cell 1 (NFATc1) gene hypomethylation was also identified and was further shown to be associated with increased mRNA and protein expression, suggesting hypomethylation as a mechanism of constitutive activation of NFATc1 expression in CLL. Through subsequent findings, however, it was discovered that the activation of oncogenes through DNA hypomethylation was a rather infrequent lesion in CLL [25].

To date, several studies have reported gene promoter hypermethylation in CLL patients using both global and single gene approaches. The affected genes include tumor suppressors, transcription factors, genes involved in survival and proliferation, genes with prognostic impact, and microRNA genes. There are several methods that have been used to study gene methylation in chronic lymphocytic leukemia. Each approach has its own advantages and limitations, and the choice of the method depends on the specific research question being addressed. Bisulfite sequencing is considered the gold standard method for analyzing DNA methylation at single-nucleotide resolution. Bisulfite treatment of DNA converts unmethylated cytosine to uracil, while leaving methylated cytosine unchanged. After polymerisation chain reaction (PCR) amplification and sequencing, the pattern of cytosine-to-thymine conversion can be used to determine the methylation status of individual CpG sites. Methylation-specific PCR is a PCR-based method that uses primers specific for either methylated or unmethylated DNA to amplify a region of interest. By comparing the intensity of PCR products amplified using methylated-specific versus unmethylated-specific primers, the methylation status of a given region can be determined. Infinium methylation arrays are microarray-based platforms that can interrogate the DNA methylation status of thousands of CpG sites across the genome. Infinium arrays rely on bisulfite conversion of DNA, followed by hybridization with probes that distinguish between methylated and unmethylated DNA at each CpG site. Methylation-sensitive restriction enzyme digestion relies on the use of restriction enzymes that are sensitive to DNA methylation. By digesting genomic DNA with these enzymes and comparing the resulting fragment patterns with and without prior treatment with a DNA methyltransferase, the methylation status of specific regions can be inferred.

2. The CLL Methylome from a Gene-Specific Perspective

Early in 2004, using genome-wide screening for aberrant promoter methylation in CLL samples, 193 sequences were identified as novel targets for aberrant methylation in CLL. Among them, 173 were homologous to specific genes such as glutamate metabotropic receptor 7 (GRM7), cell division protein kinase 6 (CDK6), T-box transcription factor 3 (TBX3), paired box 5 (PAX5), and protein tyrosine phosphatase nonreceptor type 1 (PTPN1) genes [19]. In another study, where DNA methylation was compared within immunoglobulin heavy-chain gene variable region (IGVH) mutated/unmutated subgroups of CLL, it was reported that in IGVH-unmutated cells, tumor suppressor genes such as von Hippel–Lindau (VHL), Abelson interactor 3 (ABI3), and immunoglobulin superfamily member 4 (IGSF4) were found hypermethylated while genes associated with cell proliferation and migration such as adenosine A3 receptor (ADORA3) and perforin 1 (PRF1) were hypomethylated [26].

Regarding microRNAs, a genome-wide profiling in CLL patients led to the detection of 128 microRNAs carrying aberrantly methylated promoters. Hypermethylated loci included the promoter regions of miR-9-2, miR-124-2, miR-129-2, miR-551b, and miR-708, while miR-21, miR-29a/b-1, miR-34a, miR-155, miR-574, and miR-1204 gene promoters were found hypomethylated [27].

When DNA methylation was studied in paired diagnostic and follow-up samples from IGVH mutated and unmutated CLL patients, genes with prognostic significance including chronic lymphocytic leukemia upregulated 1 (CLLU1), lipoprotein lipase (LPL), zeta chain of T-cell receptor-associated protein kinase 70 (ZAP70) and NOTCH1, the epigenetic regulators histone deacetylases 9 and 4 (HDAC9/4), and DNA methyltransferase 3, beta (DNMT3B), were reported to be aberrantly methylated [14]. Another study used the methylation levels of five specific CpGs to track the cellular origin of CLL, where they seemed to act as enhancers. The varying methylation levels of these biomarkers did not translate into gene expression changes, suggesting that they may not have a functional impact but represented a stable molecular mark [28].

In the context of normal B-cell maturation, CLL DNA methylation was reported to be highly enriched in enhancer and promoter regions, especially in regions of transcriptional elongation and in genes involved in B cell- and lymphocyte-related processes and pathways. Regions targeted for hypomethylation during B cell maturation showed highly significant enrichment for the following six transcription factor families: activator protein 1 (AP-1), early B-cell factor (EBF), runt-related transcription factor (RUNX), octamer-binding transcription factor (OCT), interferon regulatory factor (IRF), and NF-kB [20].

In future, it will be crucial to further develop more efficient and accurate prognostic tools that incorporate clinical, cytogenetic, and molecular data. Therapeutic strategies and agent design are constantly reformed in order to pursue discoveries about the biology of the disease, the pathways involved, and the mechanisms of drug resistance.

To capture the latest discoveries, this review focuses on the present knowledge about single gene/gene promoter methylation in CLL biology while also recording older data that have been published in past papers. Through a review of 126 articles indexed in PubMed, we ended up recording data for 133 genes. Then, we classified them in the following tables according to their associated biological pathways and the related data on CLL studies. It is reasonable for several genes to be associated with more than one pathway. Α characteristic attempt to capture the correlations between most genes and pathways is presented in Figure 1.

In the following tables are presented the genes we identified in our search, with information on their function, as well as the findings of studies regarding CLL. In each table, we introduced in detail, data on the study of methylation or mRNA expression of single genes in CLL patients that showed interesting correlations with clinical and laboratory data.

2.1. Chromosome Maintenance and the Cell Cycle Process

2.1.1. SE Translocation and MYN Domain Containing 3 (SMYD3) and Human Telomerase Reverse Transcriptase (hTERT) Genes (Table 1)

SMYD3 is a chromatin modifier that is involved in the development and progression of several malignancies. Methylation levels in specific SMYD3 gene promoter CpG sites were reported to independently predict time to treatment [29].

Hypermethylation of the hTERT gene in CLL was one of the first to be described. TERT acts as a subunit of telomerase, preventing chromosomal degradation after DNA replication. It was reported that hTERT promoter hypermethylation led to decreased telomerase activity and was associated with superior overall survival [30].

2.2. DNA Repair Mechanisms and Purine Biosynthesis

2.2.1. Ribonucleotide Reductase Subunits 1 and 2 (RRM1 and RRM2) Genes (Table 2)

Ribonucleotide reductase is required for DNA replication and repair and consists of RRM1 and RRM2 proteins. In CLL patients, RRM1 mRNA expression was higher in patients without anemia, absence of lymphadenopathy, and 17p gene deletion. Moreover, abnormal lactate dehydrogenase (LDH) levels and higher Rai stage were associated with lower RRM1 mRNA levels. Higher expression of RRM2 mRNA was detected in patients without lymphadenopathy, Rai stage 0, and trisomy 12. The methylated status of RRM1 promoter significantly correlated with lymphadenopathy presence. The methylated status of RRM1 promoter correlated also with about 4 times lower levels of RRM1 mRNA and with about 10 times lower levels of RRM2 mRNA [39].

2.3. Gene Transcription

2.3.1. Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA-4) Gene (Table 3)

CTLA-4 protein is involved in gene transcription and acts as an immune checkpoint to regulate T-cell function. Mutations in its gene have been associated with insulin-dependent diabetes mellitus, Grave's disease, Hashimoto thyroiditis, celiac disease, systemic lupus erythematosus, and other autoimmune diseases. In CLL cases, CTLA4 gene was hypomethylated in the first exon region and body region. Compared to healthy controls, CTLA4 gene had a 128-fold higher expression in CLL samples [37, 59].

2.4. RNA Polymerase I Promoter Opening

2.4.1. V-Maf Musculoaponeurotic Fibrosarcoma Oncogene Homolog B (MAFB) Gene (Table 4)

MAFB gene has been associated with survival parameters in CLL cohorts where differentially hypermethylated regions correlated with inferior post-treatment survival. The protein encoded by MAFB gene is a basic leucine zipper (bZIP) transcription factor with an important role in the regulation of hematopoiesis and nervous system development [66].

2.5. Programmed Cell Death/Cell Apoptosis and p53 Signaling

2.5.1. Integrin Subunit Alpha 4 (ITGA4) Gene (Table 5)

ITGA4 is capable of cell adhesion molecules and fibronectin binding and is involved in apoptotic and integrin pathways. It is reported to be deregulated in CLL with adverse clinical features, suggested as a negative prognostic factor related to a more aggressive course and shorter time to treatment. Protein expression is regulated at the mRNA level and in a methylation-regulated manner. Hypermethylation at specific ITGA4 CpG sites was a common phenomenon in the del13q14+ samples. Moreover, it was demonstrated that the methylation status of the ITGA4 gene at CpG site 1 may have a prognostic role [70].

2.6. Transforming Growth Factor-β (TGF-β) Pathway

2.6.1. Doublecortin-Like Kinase 2 (DCLK2) and Tumor Necrosis Factor Receptor Superfamily Member 1B (TNFRSF1B) Genes (Table 6)

Retrotransposons (also referred as class I transposable elements or transposons through RNA intermediates) are a type of genetic component that copy and paste themselves into different genomic locations (transposons) by retroconverting RNA into DNA via the reverse transcription process using RNA transposition intermediate. In solid neoplasms, universal hypomethylation of these elements has been described. In CLL, locus-specific hypomethylation was detected with differential expression of proximal genes, including DCLK2 and TNFRSF1B genes. Moreover, higher levels of DCLK2 and TNFRSF1B expression were associated with inferior survival. DCLK2 protein is characterized by transferase and protein tyrosine kinase activity, whereas TNFRSF1B protein by ubiquitin protein ligase binding and tumor necrosis factor (TNF) receptor activity. Both proteins are involved in TGF-β and TNF pathways [88].

2.7. Wingless-Related Integration Site (WNT) and Hedgehog Pathways

2.7.1. WNT Family Member 5A (WNT5A) Gene (Table 7)

WNT5A gene encodes a receptor tyrosine kinase-like orphan receptor (ROR1) ligand with DNA-binding transcription factor activity and is involved in the regulation of p21 activated kinase 2 (PAK-2), WNT signaling, and developmental pathways during embryogenesis. It is known that its expression differs in CLL patients with worse prognosis in the IGVH-mutated subgroup. Methylation levels of all CpG sites in the WNT5A gene promoter were lower in the group of the intermediate genome methylation profile. In the memory-like and intermediate genome methylation profile groups, promoter methylation and subsequent undetectable WNT5A expression correlated with longer treatment-free survival [95].

2.8. NFAT and T-Cell Receptor (TCR) Signaling

2.8.1. NFATC1 Gene (Table 8)

NFATC1 is part of the NFAT transcription complex. It is primarily involved in gene transcription during the immune response and acts as a downstream regulator of the BCR signaling pathway. As with many other proteins, alternative splicing leads to multiple transcription variants, which in turn may induce the expression of different cytokine genes. Moreover, NFATC1 protein is a central target for immunosuppressive agents. Regarding CLL, when the genome-wide DNA methylation study was performed, NFATC1 gene was reported to be hypomethylated and upregulated. Moreover, NFATC1 gene promoter DNA hypomethylation correlated inversely with RNA levels and was associated with Binet disease staging and thymidine kinase levels, suggesting a potential central role of NFATC1 in CLL pathobiology [105].

2.9. NF-kB Pathway

2.9.1. Leucine Zipper Was Downregulated in Cancer 1 (LDOC1) Gene (Table 9)

LDOC1 gene encodes a leucine zipper protein and is suggested to regulate the NF-κB pathway through the plasma membrane ATPase or TNF-mediated pathway of apoptosis. Its expression has been studied in oral squamous cell carcinoma and pancreatic cancer cells. Regarding CLL, unmethylated status was found in IGVH-unmutated cases [26, 111, 112].

2.10. MAPK/Erk Pathway

2.10.1. Angiopoietin 2 (ANGPT2) Gene (Table 10)

ANGPT2 is a glycoprotein involved in angiogenesis. Conflicting data regarding the involvement of Erkand phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathways in the regulation of ANGPT2 suggest a possible cell-type specific control for this gene in solid tumors. As regards CLL, higher levels of ANGPT2 methylation in the IGHV-mutated population showed a possible epigenetic regulation of this gene. Furthermore, it was reported that ANGPT2 expression is highly dependent on the DNA methylation status, where a lower degree of methylation was associated with a particularly poor prognosis in CLL. Importantly, the percentages of methylation showed negative correlations with ANGPT2 mRNA expression, suggesting that methylation of the ANGPT2 promoter leads to this gene silencing. CLL cases with highly methylated gene status had a more favorable prognosis. Considering that normal B cells showed high levels of ANGPT2 methylation, the apparently aberrant low ANGPT2 methylation levels found in aggressive CLL patients indicate that these latter cases lose normal epigenetic control [14, 119–121].

2.11. NOTCH Signaling

2.11.1. CREBBP (cAMP Response Element-Binding Protein Binding Protein) Gene (Table 11)

In a small Korean cohort, genome-wide methylation profiling identified the CREBBP gene with no known relevance to CLL to be differentially methylated among other genes previously known to be affected in CLL. CREBBP gene encodes chromatin-modifying enzymes and has been described in diffuse large B cell lymphoma, acute lymphoblastic leukemia, and lung cancer [130].

2.12. JAK-STAT Pathway

2.12.1. SOCS-1 (Suppressor of Cytokine Signaling 1) Gene (Table 12)

SOCS-1 is an inhibitor of cytokine signal transduction. Its gene expression can be positively affected by interleukins 2 and 3, erythropoietin, granulocyte macrophage colony-stimulating factor, and interferon-gamma. Gene polymorphisms of SOCS1 and its expression have been studied in several malignancies including diffuse large B-cell lymphoma and acute lymphoblastic leukemia, where, particularly, the expression level of SOCS1 was lower compared to the control group. In CLL, the SOCS1 gene body was hypermethylated in no case [135].

2.13. Phosphatidylinositol-3 Kinase/Protein Kinase B (PI3K/Akt) Signaling

2.13.1. T-Cell Leukemia/Lymphoma 1 Oncogene (TCL1A) Gene (Table 13)

Abnormal expression of TCL1A gene in mouse B-cells led to a leukemia phenotype similar to aggressive human CLL. It is demonstrated that TCL1A physically interacts with DNA methylthansferases 3A and 3B. TCL1A is suggested to act as a coactivator of Akt, activator protein 1 (AP1), and NF-κB pathways with a potential involvement in CLL cells resistance to apoptotic mechanisms. TCL1A expression seems to be strongly associated with the expression levels of ataxia-telangiesctasia mutated (ATM) gene in malignant and nonmalignant B cells. TCL1A gene promoter was hypomethylated in CLL cells and significantly correlated with TCL1A transcription enhancement [139].

2.14. Rho GTPases/Rhodopsin-Like Receptors

2.14.1. Endothelin-1 (ET-1) Gene (Table 14)

This gene is responsible for the creation of a peptide that belongs to the endothelin/sarafotoxin family. This peptide acts as a potent vasoconstrictor and its receptors have been well studied as therapeutic targets in the treatment of pulmonary arterial hypertension. Regarding ET-1 gene expression, alternative splicing leads to several transcript variants and abnormal expression is thought to promote tumorigenic activity, with ET-1 expression being under the constant control of the NF-kB signaling pathway. In CLL, ET-1 is reported to be involved in survival, drug resistance, and growth signaling of leukemic cells. Moreover, it is reported that basal expression levels of ET-1 are affected when high methylation in the region of ET-1 gene first intron is detected [141].

2.15. Class I Major Histocompatibility Complex (MHC)-Mediated Antigen Processing

2.15.1. Ubiquitin Conjugating Enzyme E2 R2 (UBE2R2) Gene (Table 15)

UBE2R2 is involved in Class I MHC-mediated pathways as well as in the metabolism of certain proteins. To develop a tool useful in stratifying CLL patients on a specific methylation signature basis and focusing on time to treatment, it was demonstrated that UBE2R gene methylation levels independently predicted time to treatment [29].

2.16. Estrogen Receptor (ESR)-Mediated Signaling

2.16.1. Estrogen Receptor 1 (ESR1) Gene (Table 16)

ESR1 gene encodes a ligand-dependent transcription factor. ESR1 acts through direct binding to specific estrogen response elements and is associated with other transcription factors. ESR-mediated signaling has been studied in several solid tumors and hematological malignancies. When studied in CLL samples, ESR1 gene was amplified in 15% of the samples examined with a copy number loss frequency ranging between 1 and 10%. The ESR1 gene promoter region was methylated in one out of ten CLL samples controlled, and in normal B cell, the gene promoter was completely unmethylated [51].

2.17. Angiogenesis/Erythropoiesis

2.17.1. Thrombospondin-1 (THBS1) Gene (Table 17)

THBS1 acts as an adhesion-specific glycoprotein. THBS1 is able to bind fibrinogen, fibronectin, laminin, and type V collagen and is involved in platelet aggregation, angiogenesis, and tumorigenesis. In CLL studies, THBS1 gene promoter methylation was detected in 50% of the samples, while in normal samples, the gene promoters were unmethylated [51].

2.18. Slit Glycoprotein/Roundabout Receptor (SLIT/ROBO) Signaling and Nervous System Development

2.18.1. Protein Tyrosine Phosphatase Type O (PTPRO) Gene (Table 18)

The methylation levels of the PTPRO gene have been studied in the pathobiology of several neoplasms including hepatocellular cancer and various lung tumors, with indications of potential tumor suppressor features. Regarding CLL, PTPRO gene promoter was also methylated and gene expression was suppressed compared to normal B cells, with the overall expression of PTPRO being lower in CLL lymphocytes than in normal samples [51].

2.19. Drug Uptake and Sensitivity Mechanisms

2.19.1. Solute Carrier Family 22 Member 18 (SLCO3A1) Gene (Table 19)

Methylation of the SLCO3A1 gene has been associated with survival features in CLL cohorts where specific differentially hypermethylated regions were linked to inferior post-treatment survival. SLCO3A1 gene encodes an anion transporter that is suggested to be involved in transport of inorganic cations/anions and amino acids/oligopeptides, transport of vitamins, nucleosides, and related molecules, as well as drug uptake mechanisms [66].

2.20. Various Other Genes Investigated

2.20.1. GATA-Binding Protein 5 (GATA5) Gene (Table 20)

GATA5 contains two GATA-type zinc fingers and is related to hepatocyte nuclear factor-1alpha. Promoter methylation of the GATA5 gene has been involved in gastric cancer biology. When studied in CLL, GATA 5 gene hypermethylation was detected in 35.1% of the cases. Another study reported that genomic regions which became hypomethylated prior to specific CLL treatment initiation but also after disease relapse were enriched for binding sites of several transcription factors related to CLL pathogenesis, including GATA5. Compared to normal B-cells, these hypomethylated regions were also enriched for the GATA 5 transcription factor [51, 167].

2.20.2. SH3 and Multiple Ankyrin Repeat Domain 1 (SHANK1) Genes (Table 20)

SHANK1 gene encodes a protein acting as a scaffold molecule required for the development and function of neuronal synapses. In CLL samples, a specific CpG region of the SHANK1 gene body (hg19) was reported to be hypermethylated when compared to control samples. Moreover, without yet being strongly supported, it was reported that methylation in the same CpG was detectable in blood samples collected years before CLL diagnosis [170].

2.20.3. RalA-Binding Protein-Associated Eps Domain Containing 1 (REPS1), Interleukin 1B (IL1B), and ATPase Phospholipid Transporting 9B (ATP9B) Genes (Tables 21 and 22)

Specific CpG sites at which the methylation levels independently predicted time to treatment were detected and some of them located in the gene bodies of REPS1, IL1B, and ATP9B. REPS1 protein has calcium ion and SH3 domain-binding activity with involvement in vesicle transport and endocytosis. IL1B protein has interleukin-1 receptor-binding activity and is involved in MIF-mediated glucocorticoid regulation. ATP9B protein is capable of nucleotide binding and ATPase-coupled monoatomic cation transmembrane transporting and is involved in ion channel transport and cardiac conduction mechanisms [29].

2.21. Noncoding RNAs

2.21.1. Colorectal Neoplasia Differentially Expressed (CRNDE) Gene (Table 23)

The expression of the CRNDE gene is increased in proliferating tissues and is involved in the expression of genes associated with metabolism and in neoplasms such as colorectal adenomas and adenocarcinomas. Its related transcription is inversely regulated by insulin and insulin-like growth factors. When studied in CLL cell lines, CRNDE was downregulated and the methylation level of CRNDE promoter was higher than in normal B cells. After exposure to demethylating agents, an increase of CRNDE expression levels was reported [183].

3. Conclusion

Some studies have focused on the potential clinical impact of DNA methylation in CLL phenotypes. Based on the findings abovementioned, time to treatment, an essential feature of CLL management, was reported to be predicted by the methylation status of SMYD3 gene promoter and UBE2R gene methylation levels [29]. Methylation levels in specific CpG sites located in the gene bodies of REPS1, IL1B, and ATP9B genes also correlated with the time to treatment [29].

Regarding overall survival, hTERT gene promoter hypermethylation was associated with superior overall survival [30], and specific hypermethylated MAFB gene loci correlated with inferior post-treatment survival [66]. Moreover, locus-specific hypomethylation of retrotransposons proximal to DCLK2 and TNFRSF1B was related with higher levels of DCLK2 and TNFRSF1B expression and subsequent inferior survival [88]. When CLL patients were classified upon specific IGVH mutation patterns, promoter methylation of the WNT5A gene showed longer treatment-free survival in a subgroup of the patients [95]. Lower levels of DNA methylation of the ANGPT2 gene were related to a particularly poor prognosis in CLL patients [14, 121].

Findings that could be useful in staging and correlating methylation with pre-existing prognostic factors in CLL include RRM1/2 expression, the promoter methylation status that correlated with lymphadenopathy, 17p gene deletion, Rai stage, and trisomy 12 [39], and the documentation of hypermethylation at specific ITGA4 CpG sites in del13q14+ samples [70]. NFATC1 gene promoter hypomethylation was associated with Binet disease staging [105].

Drug sensitivity and mechanisms of resistance development are another important area of study in CLL. Hypermethylation of specific SLCO3A1 gene loci, a gene which among others is involved in drug uptake mechanisms, has also been associated with inferior post-treatment survival [66]. Another gene, ET-1, is related with drug-resistance potential and its expression is affected upon high methylation levels in its first intron region in patients with CLL [141].

Α last finding that could theoretically have a clinical application in CLL cases is about the SHANK1 gene. A specific CpG locus of its body (hg19) was hypermethylated when compared to control samples. Also, it was even weakly supported that methylation in the same CpG was detectable in blood samples collected years before CLL diagnosis [170]. It is a finding that, if confirmed, is very interesting and could be used in panels for early diagnosis of the disease, certainly in combination with other markers in the context of a population screening program or the surveillance of high-risk patients. Certainly, such methods of investigation have their peculiarities and must be applied after appropriate research and discussion in order to be necessary or beneficial for the patients.

Our findings suggested that certain methylation patterns have been associated with disease progression and survival features and may be used as prognostic markers. In addition, some studies have investigated the use of hypomethylating agents as a part of a therapeutic strategy in CLL.

Regarding findings from previous studies that focused on studying large numbers of genes, data are generally limited but quite intriguing. Kanduri et al. applied high-resolution methylation microarrays (27 578 CpG sites) to CLL samples, which were classified in IGHV-mutated (favorable) and IGHV-unmutated/IGHV3-21 (poor-prognostic) subsets. Results demonstrated significant differences in methylation patterns between these subgroups. In IGHV-unmutated cases, they reported methylation of known or potent tumor suppressor genes (for example, VHL, ABI3, and IGSF4) as well as unmethylated genes involved in cell growth and tumor progression (ADORA3 and PRF1). In contrast, these latter genes were silenced by methylation in IGHV-mutated patients. Moreover, they reported the reinducing of four methylated tumor suppressor genes (including VHL and ABI3) in IGHV-unmutated samples using the methyl inhibitor 5-aza-2′-deoxycytidine [26]. Pei et al. reported a genome-wide DNA methylation analysis with 1,764 gene promoters being identified as differentially methylated in at least one sample when compared with normal B cell samples. Aberrant hypermethylation was discovered in all HOX gene clusters and a significant number of WNT signaling pathway genes. The NFATc1p2 promoter and first intron hypomethylated status correlated with the upregulation of both NFAT protein expressions [25]. Kulis et al. performed a wide analysis of the DNA methylome in normal B cells and CLL samples. They identified widespread hypomethylation targeting mainly the gene body and enhancer regions, suggesting that DNA methylation may be functionally relevant beyond promoter regions. Moreover, they reported that distinct patterns in DNA methylation were recorded between different CLL subtypes [18]. Cahill et al. used high-resolution 450 K arrays to analyze samples from IGHV-mutated or untreated and IGHV-unmutated or treated patients. They identified 2239 differentially methylated CpG regions between IGHV-mutated and -unmutated patients, where the majority of the regions were placed outside annotated CpG islands. Known CLL prognostic genes (i.e., LPL, ZAP70, and NOTCH1), epigenetic regulators (HDAC9/4 and DNMT3B), B-cell signaling, and numerous TGF-β and NF-κB/TNF pathway genes were differentially methylated between the subgroups [14]. Barrow et al. reported 490 differentially methylated regions after exposure to therapy. Among them, 31 were CLL related. Seventeen genes were classified as differentially expressed, following treatment in an independent cohort. Methylation of the HOXA4, MAFB, and SLCO3A1 differentially methylated regions associated with post-treatment patient survival and HOXA4 displayed the strongest association. Reinducing of HOXA4 expression in cell lines and primary CLL cells increased apoptosis following treatment with fludarabine, ibrutinib, and idelalisib [66]. Lastly, Zhang et al. identified 34,797 differentially methylated positions related to CLL. Most of them were hypomethylated and located in gene body sites. They combined these positions with existing DNA methylation and RNA sequencing data and identified regions associated with 1,130 genes whose expression was significantly different in CLL samples [37].

The limitations of this study include possible evidence selection bias because data from statistically significant studies are more likely to be published than those that are not statistically significant. Moreover, in some limited reports, it was not stated whether the methylation study included the gene body, the promoter region, or some other related loci. Lastly, some papers did not reported correlations with patients' clinical data such as sampling time, staging, or prognostic and treatment features.

To summarize, there are still many mechanisms that need to be investigated in order to define the extent of global aberrant DNA methylation in different prognostic groups, the fundamental role of DNA methylation in sites other than CpG islands, and the interaction of DNA methylation with other regulatory processes in the pathogenesis of CLL. Moreover, with the prospect that there is and will continue to be increasing data on gene methylation, it should be noted that a large number of findings will concern passenger DNA methylation events that need to be identified accordingly.

In conclusion, at some points, the research raises even more questions than answers. Further research is still needed to fully understand the complex interplay between DNA methylation and other epigenetic and genetic alterations in CLL and to develop more effective targeted therapies and prognostic stratification tools for this disease.

Data Availability

The datasets used to support the findings of this study are available from the corresponding author on reasonable request.

Disclosure

Citations are included in the reference list.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors' Contributions

SC and N-AV had the idea for the article. SC performed the literature search and wrote the first draft of the manuscript. N-AV critically revised the work. All the authors have discussed the results, drafted further work, and approved the version to be published. All the authors have agreed to be responsible for the accuracy and integrity of any part of the manuscript.

Figure 1 Schematic representation of the interaction between genes and major biological pathways (created with GitMind®: https://gitmind.com/).

Table 1 Chromosome maintenance and cell cycle process.

Gene names	Related pathways	Findings in CLL	Ref.	
SMYD3	Chromatin organization	Methylation levels in specific CpG sites independently predicted time to treatment	[29]	
hTERT	Chromosome maintenance signaling by WNT	Promoter hypermethylation was associated with superior overall survival	[30]	
CDKN2A/2B	Capable of inducing cell cycle arrest in G1 and G2 phases and regulation of activated PAK-2 gene expression (transcription)	Both genes' promoters have been found variously hypermethylated in CLL cases among different studies; common point of these studies was that hypermethylation of CDKN2A and CDKN2B was mutually exclusive in CLL cases	[31–34]	
KLF4	G1-to-S transition of the cell cycle after DNA damage through p53 gene expression (transcription), NOTCH	Aberrant methylation of the KLF4 promoter was significantly associated with gene expression levels compared to normal samples after B cell activation, KLF4 expression was reported to be downregulated	[35]	
PTPN6	Cell growth, differentiation, mitotic cycle, and oncogenic transformation	In advanced Rai stage cases, aberrant methylation of PTPN6 promoter reached 70% in the samples examined	[36]	
AGBL4	Metabolism of proteins actin and tubulin folding	AGBL4 expression was reported to be reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 38]	
CLL: chronic lymphocytic leukemia, Ref.: reference, SMYD3: SE translocation and MYN-domain containing 3 protein, hTERT: human telomerase reverse transcriptase, CDKN2A/2B: cyclin-dependent kinase inhibitors 2A and 2B, KLF4: Krüppel-like factor 4, PTPN6: tyrosine-protein phosphatase nonreceptor type 6, AGBL4: ATP/GTP binding protein like 4, WNT: wingless-related integration site, PAK-2: P21 activated kinase 2, NOTCH: neurogenic locus notch homolog protein.

Table 2 DNA repair mechanisms and purine biosynthesis.

Gene names	Related pathway	Findings in CLL	Ref.	
RRM1 and RRM2	Pyrimidine deoxyribonucleotides biosynthesis and purine nucleotides de novo biosynthesis	RRM1 mRNA expression was higher in patients without anemia, absence of lymphadenopathy and 17p gene deletion, abnormal LDH and higher Rai stage were reported to be associated with lower RRM1 mRNA levels, and higher expression of RRM2 mRNA was detected in patients without lymphadenopathy, Rai stage 0, and trisomy 12	[29, 39]	
RAD21	Separation of sister chromatids and cell cycle DNA repair mechanisms	There are differences in RAD21 promoter methylation proportion among patients, RAD21 inactivation via methylation may affect DNA repair mechanisms and amplify self-renewal potential of CLL cells	[40–45]	
MGMT and hMLH1	DNA damage reversal homology-directed repair	MGMT promoter region was rarely identified to be hypermethylated, and hMLH1 promoter was reported to be hypermethylated in a small case series of indolent CLL with later Richter's transformation	[32, 46–50]	
FHIT	Loss of its activity results in replication stress and DNA damage	In a limited series of CLL cases studied, FHIT promoter was reported to be hypermethylated	[51–53]	
GSTP1	Important regulatory features in detoxification, antioxidative damage innate immune system	GSTP1 promoter hypermethylation was reported in 2.7% of the samples controlled	[51, 54–56]	
MACROD2	DNA damage response purine nucleoside metabolic process	MACROD2 expression was demonstrated to be lower in cases with hypermethylated promoter regions and hypomethylated body regions	[37, 57]	
ADORA3	Activation of the NF-kB pathway, purinergic signaling, GPCR signaling	Methylated gene body is reported in IGVH-mutated cases	[26, 58]	
CLL: chronic lymphocytic leukemia, Ref.: reference, RRM1: ribonucleotide reductase subunit 1, RRM2: ribonucleotide reductase subunit 2, RAD21: double-strand-break repair protein rad21, MGMT: methylguanine methyltransferase, hMLH1: human mutL homolog 1, FHIT: fragile histidine triad, GSTP1: glutathione S-transferase p1 gene, MACROD2: mono-ADP ribosylhydrolase 2, ADORA3: adenosine A3 receptor, NF-kB: Nuclear factor kappa B, GPCR: G protein-coupled receptor, LDH: lactic dehydrogenase, IGVH: immunoglobulin variable heavy chain gene.

Table 3 Gene transcription.

Gene names	Related pathway	Findings in CLL	Ref.	
CTLA4	Gene expression (transcription) CD28 costimulation	CTLA4 was hypomethylated in the first exon region and body region and had 128-fold higher expression compared to healthy controls	[37, 59]	
LMO2	Angiogenesis and erythropoiesis gene expression (transcription), Assembly of the pre-replicative complex	LMO2 gene body methylated status was identified in IGVH-mutated samples	[26, 60–62]	
RARb2	Angiogenesis and erythropoiesis gene expression (transcription), Assembly of the prereplicative complex	Hypermethylation of RARbCpG islands was identified in 29.7% of the analyzed samples in a group of patients while in another series, it was found in 3.1% of the samples studied	[32, 51, 63]	
CAT	Gene expression (transcription) innate immune system oxidative stress	A distal CpG island in the promoter region remained methylated both in normal B cells and CLL cells, while variable methylation levels were recorded in the proximal CpG island only in CLL cells exposure of CLL cells to a demethylating agent led to increased catalase mRNA levels	[64]	
ZNF540	Gene expression (transcription) MAPK pathway	Methylated status of its gene body was reported in IGVH-unmutated cases	[26, 65]	
CLL: chronic lymphocytic leukemia, Ref.: reference, ZNF540: human zinc finger protein 540, LMO2: LIM-only protein 2, RARb2: retinoic acid receptor B2, CAT: catalase, CTLA4: cytotoxic T-lymphocyte associated protein 4, MAPK: mitogen-activated protein kinase, IGVH: immunoglobulin variable heavy chain gene.

Table 4 RNA polymerase I promoter opening.

Gene names	Related pathway	Findings in CLL	Ref.	
MAFB	RNA polymerase I promoter opening, nervous system development regulation of hematopoiesis	Differentially methylated regions of the MAFB gene have been associated with survival features in CLL cohorts where the hypermethylated status was linked to inferior post-treatment survival	[66]	
HOXA4	RNA polymerase I promoter opening	Hypermethylated promoter region was associated with the IGVH-unmutated status and inferior clinical outcome, strong predictor of time to first treatment, independent of the IGVH mutational and CD38 expression status	[67, 68]	
TET1	RNA polymerase I promoter opening, gene expression (transcription)	TET1 gene body was variously methylated, 5-aza 2′-deoxycytidine exposure to CLL cells led to decreased occupancy of EZH2 over the TET1 promoter and conversely to the loss of TET1 expression, increased expression of specific intronic transcripts associated with decreased TET1 promoter activity	[69]	
CLL: chronic lymphocytic leukemia, Ref.: reference, MAFB: V-maf musculoaponeurotic fibrosarcoma oncogene homolog B, HOXA4: homeobox A4, TET1: tet methylcytosine dioxygenase 1, CD38: cluster of differentiation 38, EZH2: enhancer of Zeste 2 polycomb repressive complex 2 subunit, IGVH: immunoglobulin variable heavy chain gene.

Table 5 Programmed cell death/cell apoptosis and p53 signaling.

Gene name	Related pathway	Findings in CLL	Ref.	
ITGA4	Apoptotic pathways and integrin pathway	Protein levels are related to more aggressive course and shorter time to treatment, protein expression is regulated at the mRNA level and in a methylation-regulated manner, hypermethylation at specific ITGA4 CpG sites was shown to be a common phenomenon in the del13q14+ samples, and the methylation status of ITGA4 at CpG site 1 was demonstrated to be have a prognostic role	[70]	
S100A14	Modulates TP53 protein levels MAPK-Erk NF-kB	Unmethylated gene body status was found in IGVH-unmutated samples	[26, 71, 72]	
TP53I3	Gene expression (transcription), TP53-mediated transcription of cell death genes	Gene methylated gene body status was reported in IGVH-mutated cases, patients showed the unmethylated TP53 gene promoter status, and TP53 promoter methylation significantly correlated to reduced platelet counts and advanced stage at diagnosis	[26, 73–76]	
p73	TP53-mediated transcription of cell death genes; gene expression (transcription)	Protein expression correlated positively with higher risk of CLL stages; regarding p73 hypermethylation, there are conflicting results from different studies showing that pathways other than isolated regulation of p73 activity are responsible for CLL pathogenesis	[32, 77–79]	
TP63	TP53-mediated transcription of cell death genes; gene expression (transcription)	TP63 gene was primarily hypomethylated in the promoter region and overexpressed in a subset of IGVH-unmutated samples with the highest risk for Richter's transformation. BCR stimulation in that group of CLL cases led to protein induction and increased cell survival	[80]	
TIMP-2/3	GPCR signaling	TIMP-2 and TIMP-3 generally lack hypermethylation	[32, 81, 82]	
NGFR	Antiproliferative signals transmission, p75 NTR receptor-mediated signaling	NGFR gene body was reported to be unmethylated in IGVH-mutated cases	[26, 83]	
ITGB2	Apoptotic pathways integrin pathway	The grade of methylation was negatively associated with CD18 surface expression; high grade of ITGB2 promoter methylation was found in CLL samples with low CD18 expression, whereas high CD18 expressing CLL cells; in the trisomy 12 subgroup, they were mainly unmethylated at the same region; when proliferating and nonproliferating cells were compared, the ITGB2 promoter methylation was similar among these groups	[84]	
OSM	MIF-mediated glucocorticoid regulation, Erk signaling	In a study where cells from CLL, Richter's transformed CLL, and normal B cells were analyzed, OSM displayed significantly higher promoter methylation levels in Richter's syndrome compared to the other groups	[85]	
MET	Apoptotic pathways, GPCR signaling	MET expression was reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 86]	
TWIST2	Gene expression (transcription), regulation of activated PAK-2 negative regulator of p53	Promoter methylation was reported in IGVH-mutated cases	[87]	
CLL: chronic lymphocytic leukemia, Ref.: reference, NGFR: nerve growth factor receptor, S100A14: S100 calcium binding protein A14, TP53I3: tumor protein P53 inducible protein 3, p73: a, TP63: tumor protein 63, TIMP-2/3: tissue inhibitors of metalloproteinase 2 and 3, ITGA4: integrin subunit alpha 4, ITGB2: integrin subunit beta 2, OSM: oncostatin M, MET: mesenchymal epithelial transition receptor tyrosine kinase, TWIST2: twist family basic helix-loop-helix transcription factor 2, p75: p75 neurotrophin receptor, NTR: neurotrophin receptor, TP53: tumor protein 53, MAPK-Erk: mitogen-activated protein kinase—extracellular signal-regulated kinases, NF-kB: nuclear factor kappa-beta, GPCR: G protein-coupled receptor, PAK-2: P21 activated kinase 2, BCR: B cell receptor gene, del: deletion, CD18: cluster of differentiation 18, IGVH: immunoglobulin variable heavy chain gene.

Table 6 TGF-β pathway.

Gene name	Related pathway	Findings in CLL	Ref.	
DCLK2 and TNFRSF1B	TGF-β pathway, TNF superfamily-associated functions	Locus-specific hypomethylation of retrotransposons proximal to DCLK2 and TNFRSF1B was detected and higher levels of DCLK2 and TNFRSF1B expression were associated with inferior survival	[88]	
BCL2	MIF-mediated glucocorticoid regulation, TGF-β pathway	Methylated BCL2 gene body has been reported in IGVH-mutated patients	[26, 89]	
IL17RC	NF-kB MAPK pathway	Unmethylated gene body status was identified in IGVH-unmutated patients	[26, 90]	
WT1	Transcription suppressor of multiple proteins including M-CSF, TGF-β, and RAR-a	WT1 expression was absent suggesting that WT1 expression was lacking in more mature cell lines; other studies revealed that WT1 promoter was methylated to a large extent of CLL patients; gene promoter regions in normal B cells were completely unmethylated	[51, 91, 92]	
FMOD	Keratan sulfate biosynthesis, TGF-β pathway, hematopoietic stem cells and lineage-specific markers, TCR signaling	FMOD was highly expressed whereas both hypomethylated gene promoter and gene body were identified	[37, 93, 94]	
CLL: chronic lymphocytic leukemia, Ref.: reference, TGF-β: transforming growth factor-β, DCLK2: doublecortin-like kinase 2, TNFRSF1B: tumor necrosis factor receptor superfamily member 1B, BCL2: B cell lymphoma 2, IL17RC: interleukin 17 receptor C, WT1: Wilms tumor 1 protein, FMOD: fibromodulin, TNF: tumor necrosis factor, MIF: macrophage migration inhibitory factor, NF-kB: nuclear factor kappa-beta, MAPK: mitogen-activated protein kinase, M-CSF: macrophage colony-stimulating factor, RAR-a: retinoic acid receptor alpha, TCR: T-cell receptor, IGVH: immunoglobulin variable heavy chain gene.

Table 7 WNT and Hedgehog pathways.

Gene name	Related pathway	Findings in CLL	Ref.	
WNT5A	Regulation of activated PAK-2, signaling by WNT developmental pathways during embryogenesis	Its expression differs in CLL patients with worse prognosis in the IGHV-mutated subgroup; methylation levels of all the CpG sites in the WNT5A promoter were lowest in the group of the intermediate genome; methylation profile in the memory-like and intermediate genome methylation profile groups were undetectable; WNT5A expression through its promoter methylation correlated with longer treatment-free survival	[95]	
WISP3	Signaling by WNT	Gene promoter was preferentially methylated in IGVH-mutated CLL	[14, 96]	
LEF1	Regulation of activated PAK-2 signaling by WNT GSK3 signaling	Methylated promoter status correlated with good prognostic features	[14, 97]	
PAX9	WNT/Hedgehog/NOTCH signaling	Higher mRNA expression was detected in IGVH-unmutated cases; high expression correlated with higher risk of treatment initiation, shorter time to first treatment, and was predictive of inferior overall survival	[98]	
WIF1, DKK3, APC, SFRP1, SFRP2, SFRP4, and SFRP5	Inhibitors of the WNT pathway	Over a half of CLL cases showed aberrant gene body methylation of at least one gene	[99–101]	
E-cad	Loss of function contributes to cancer proliferation, invasion, and/or metastasis, signaling by WNT, and regulation of CDH11	Relative to normal B cells, E-cad was minimally or even absently expressed in globally hypermethylated samples; E-cad hypermethylation was always associated with a simultaneous presence of at least one SFRP gene body hypermethylation	[32, 102, 103]	
PTCH1	Endochondral ossification signaling by Hedgehog	PTCH1 promoter was reported to be methylated in 46% of the CLL samples examined compared to no case in samples from healthy individuals	[104]	
CLL: chronic lymphocytic leukemia, Ref.: reference, WNT: wingless-related integration site, WNT5A: WNT family member 5A, WISP3: WNT inducible signaling pathway protein 3, LEF1: lymphoid enhancer-binding factor 1, PAX9: paired box gene 9, WIF1: WNT inhibitory factor 1, DKK3: Dickkopf WNT signaling pathway inhibitor 3, APC: adenomatous polyposis coli gene, SFRP1–5: secreted frizzled-related proteins 1–5, E-cad: cadherin-1, PTCH1: protein patched homolog 1, PAK-2: p21 activated kinase, GSK3: glycogen synthase kinase-3, CDH11: cadherin 11, IGVH: immunoglobulin variable heavy chain gene.

Table 8 NFAT and TCR signaling.

Gene name	Related pathway	Findings in CLL	Ref.	
CD5	Hematopoietic stem cells and lineage-specific markers, TCR signaling	CD5 has been reported to be highly expressed in CLL cells and it is demonstrated to be hypomethylated in promoter and body regions	[37, 94]	
NFATC1	Regulation of activated PAK-2, activation of cAMP-dependent PKA downstream regulator of the BCR signaling pathway	Through genome-wide DNA methylation, NFATC1 was reported to be globally hypomethylated and, therefore, upregulated NFATC1 promoter hypomethylation correlated inversely with RNA levels and was associated with Binet disease staging and thymidine kinase levels	[105]	
PRF1	Enhancer of MAPK pathway, Granzyme pathway, and TCR signaling	Methylated gene body was reported in IGVH-mutated cases	[26, 106]	
BCL10	Activation of the NF-kB pathway, regulation of activated PAK-2 TCR signaling	Unmethylated BCL gene body has been reported in IGVH-mutated patients	[26, 107]	
CLL: chronic lymphocytic leukemia, Ref.: reference, NFAT: nuclear factor of activated T-cells, TCR: T-cell receptor, CD5: cluster of differentiation, NFATC1: nuclear factor of activated T-cells 1, PRF1: perforin 1, BCL: B-cell lymphoma, PAK-2: p21 activated kinase, PKA: protein kinase A, BCR: B cell receptor, MAPK: mitogen-activated protein kinase, NF-kB: nuclear factor kappa-beta, IGVH: immunoglobulin variable heavy chain gene.

Table 9 NF-kB pathway.

Gene name	Related pathway	Findings in CLL	Ref.	
CARD15	Activation of the NF-kB pathway, MyD88-dependent cascade, MAPK activation	Gene body methylation was reported in IGVH-mutated samples	[26, 108]	
LOC340061	Activation of the NF-kB pathway, cytosolic sensors of pathogen-associated DNA	Methylated gene body status was reported in IGVH-mutated cases	[26, 109]	
UNC5CL	Inhibition of NF-kB-dependent transcription and Netrin signaling	Methylated gene body status was identified in some IGVH-mutated patients	[26, 110]	
LDOC1	Regulation of the NF-kB pathway and TNF-α-mediated pathway to apoptosis	Unmethylated gene body status was found in IGVH-unmutated cases	[26, 111, 112]	
URP2	Inhibition of NF-kB pathway, cell apoptosis response to elevated platelet cytosolic Ca2+leukocyte-intrinsic Hippo pathway	Methylated URP2 gene body correlated with IGVH-mutated cases	[26, 113]	
CLL: chronic lymphocytic leukemia, Ref.: reference, NF-kB: nuclear factor kappa-beta, CARD15: caspase recruitment domain-containing protein 15, LOC340061: early growth response 3, UNC5CL: unc-5 family C-terminal like, LDOC1: leucine zipper downregulated in cancer 1, URP2: urotensin II-related peptide, MyD88: myeloid differentiation primary response protein 88, MAPK: mitogen-activated protein kinase, TNF-α: tumor necrosis factor alpha, IGVH: immunoglobulin variable heavy chain gene.

Table 10 MAPK/Erk pathway.

Gene name	Related pathway	Findings in CLL	Ref.	
ZAP70	NFAT, TCR signaling, Rho GTPases signaling, NF-kB, Erk signaling	Negative prognostic marker in CLL methylation of a CpG site downstream of transcriptional start site correlated with IGVH-mutated and favorable prognosis	[114–118]	
ANGPT2	MIF-mediated glucocorticoid regulation, TGF-β pathway, Erk, PI3K-Akt signaling	Higher methylation levels of gene promoter in the IGVH-mutated cases, lower degree of methylation associated with particularly poor prognosis, methylation of its promoter leads to gene silencing	[14, 119–121]	
ROR1	GPCR signaling, Erk, signaling by WNT	ROR1 expression was upregulated; hypomethylation in the promoter as well as in the body region was demonstrated	[37, 122]	
DAPK1	Programmed cell death dimerization of procaspase-8, MAPK-Erk	Promoter hypermethylation associated with the downregulation of DAPK1 expression	[123]	
ADAM12	Cell-to-cell and cell-to-matrix interactions, fertilization, muscle tissue development, and neurogenesis EGFR, MAPK-Erk pathway	48% of the samples were partially methylated and 52% were reported to be unmethylated compared to 20% and 80.6%, respectively, in healthy individuals, an association statistically significant	[124]	
AIRE	Regulated by the MAPK pathway	Methylated gene body was observed in IGVH-mutated cells	[26, 125]	
RASGRP3	RAF/MAPK cascade regulation of activated PAK-2	Methylated gene body correlated with the IGVH-mutated status	[26, 126–128]	
PPP1R3A	Beta-adrenergic signaling	Methylated gene body was observed in IGVH-mutated cases	[26, 129]	
CLL: chronic lymphocytic leukemia, Ref.: reference, ZAP70: zeta chain of T-cell receptor-associated protein kinase 70, ANGPT2: angiopoietin 2, ROR1: receptor tyrosine kinase-like orphan receptor 1, DAPK1: death-associated protein kinase 1, ADAM12: disintegrin and metalloproteinase domain-containing protein 12, AIRE: autoimmune regulator, RASGRP3: rat sarcoma guanyl releasing protein 3, PPP1R3A: protein phosphatase 1 regulatory subunit 3A, NFAT: nuclear factor of activated T cells, TCR: T-cell receptor, NF-kB: nuclear factor kappa-beta, MAPK: mitogen-activated protein kinase, Erk: extracellular signal-regulated kinase, MIF: macrophage migration inhibitory factor, TGF-β: transforming growth factor beta, PI3K-Akt: phosphatidylinositol-3-kinase—protein kinase B, GPCR: G protein-coupled receptor, WNT: wingless-related integration site, RAF: rapidly accelerated fibrosarcoma, EGFR: epidermal growth factor receptor, PAK-2: p21 activated kinase 2, IGVH: immunoglobulin variable heavy chain gene.

Table 11 NOTCH signaling.

Gene name	Related pathway	Findings in CLL	Ref.	
CREBBP	Regulation of activated PAK-2, NOTCH	Genome-wide methylation profiling identified CREBBP gene body to be differentially methylated	[130]	
HDAC4/HDAC9	Notch signaling gene expression (transcription)	Gene promoter was differentially methylated between prognostic CLL subgroups	[14, 131]	
RASF10, RASF6, and KIBRA	Notch signaling regulator of the Hippo/SWH pathway	RASF10 gene promoter was frequently methylated, followed by RASF6 KIBRA gene promoter was recurrently methylated and associated with the IGVH-unmutated status and CD38 expression	[132]	
FABP7	PKC, MAPK-Erk, triglyceride metabolism, notch signaling	Methylated gene body was observed in IGVH-mutated cases	[26, 133]	
NOTCH1	Notch signaling regulation of activated PAK-2	Gene promoter methylation was associated with aggressive clinical types such as Richter's transformation and chemorefractoriness independent predictor of poor prognosis	[14, 134]	
CLL: chronic lymphocytic leukemia, Ref.: reference, NOTCH1: neurogenic locus, notch homolog protein 1, HDAC4/HDAC9: histone deacetylases 4 and 9, RASF6/RASF10: rat sarcoma-associated domain family member 6 and 10, KIBRA: kidney and brain expressed protein, FABP7: fatty acid-binding protein 7, CREBBP: cAMP response element-binding protein binding protein, PAK-2: p21 activated kinase 2, SWH: Salvador-Warts-Hippo, PKC: protein kinase C, MAPK-Erk: mitogen-activated protein kinase-extracellular signal-regulated kinase, CD38: cluster of differentiation 38, IGVH: immunoglobulin variable heavy chain gene.

Table 12 JAK-STAT pathway.

Gene name	Related pathway	Findings in CLL	Ref.	
SOCS-1	Negative regulator of type I and type II interferon and other cytokines, including IL2, IL4, IL6, and leukemia inhibitory factor; Class I MHC-mediated antigen processing and presentation; inhibitor of the JAK-STAT pathway	SOCS-1 gene body was not hypermethylated in any case	[135]	
IL19	MIF-mediated glucocorticoid regulation, TGF-β pathway, and JAK-STAT pathway	Methylated gene body was reported in IGVH-mutated CLL cells	[26, 136]	
IFNB1	Interferons-mediated signaling pathway DDX58/IFIH1-mediated induction of interferon-alpha/beta, JAK-STAT pathway	Methylated gene body was identified in IGVH-mutated samples	[26, 137]	
DUSP22	Inhibitor of MAPK and STAT pathways	Silencing of DUSP22 expression in knocked-out cells resulted in increased STAT3 activity. Targeted bisulfite sequencing and methylation-specific PCR detected that the methylation levels of the DUSP22 promoter were significantly lower in DUSP22 knocked-out cells after treatment with demethylating agents, DUSP22 promoter methylation decreased and subsequently, DUSP22 mRNA levels were increased	[138]	
CLL: chronic lymphocytic leukemia, Ref.: reference, JAK: Janus kinase, STAT: signal transducer and activator of transcription, IFNB1: interferon beta 1, IL: interleukin, SOCS-1: suppressor of cytokine signaling 1, DUSP22: dual specificity phosphatase 22, DDX58/IFIH1: DExD/H-box helicase 58/interferon induced with helicase C domain 1, MIF: macrophage migration inhibitory factor, TGF-β: transforming growth factor-beta, MHC: major histocompatibility complex, MAPK: mitogen-activated protein kinase, IGVH: immunoglobulin variable heavy chain gene.

Table 13 PI3K-Akt signaling.

Gene names	Related pathway	Findings in CLL	Ref.	
TCL1A	PI3K-Akt signaling AP1 pathway NF-kB ATM	TCL1A promoter was reported to be hypomethylated in CLL cells and correlated with significant TCL1A transcription enhancement	[139]	
PHLPP1	PIP3 signaling PI3K-Akt signaling	Low PHLPP1 expression is reported parallel with its mRNA levels; further analysis detected that the end region of exon 1 may be important in the regulation of PHLPP1 expression although low methylation was observed in the promoter region; compared with normal B cells, the CLL cells with absent or low PHLPP1 expression displayed significantly higher CpG methylation levels and more methylated CpG sites compared than normal B cells and PHLPP1-expressing CLL cells; methylation inhibition led to moderate regulation of PHLPP1 expression	[140]	
CLL: chronic lymphocytic leukemia, Ref.: reference, TCL1A: T-cell leukemia/lymphoma 1 oncogene, PHLPP1: PH domain and leucine rich repeat protein phosphatase 1, PI3K-Akt: phosphatidylinositol-3 kinase—protein kinase B, AP1: activator protein 1, NF-kB: nuclear factor kappa-beta, ATM: ataxia-telangectasia mutated, PIP3: phosphatidylinositol (3,4,5)-trisphosphate.

Table 14 Rho GTPases/Rhodopsin-like receptors.

Gene names	Related pathway	Findings in CLL	Ref.	
ET-1	GPCR signaling, class A/1 (Rhodopsin-like receptors), NF-kB	ET-1 is involved in survival, drug resistance, and growth signaling of leukemic cells; basal expression levels of ET-1 are affected when high methylation levels in a region of ET-1 first intron are detected	[141]	
PLD1	Cell survival and protection from apoptosis. Glycerophospholipid biosynthesis signaling by Rho GTPases	Unmethylated PLD1 gene body was reported in IGVH-mutated cases	[26, 142]	
DLC1	Signaling by Rho GTPases	In advanced Rai stage CLL cases, aberrant methylation of DLC1 promoter was identified in 89.7% of the samples examined	[36]	
S1PR4	Involved in cell migration, GPCR signaling, class A/1 (Rhodopsin-like receptors)	In a study where cells from CLL, Richter's transformed CLL and normal B cells were analyzed, and S1PR4 displayed significantly higher promoter methylation levels in Richter's syndrome compared to the other groups	[85]	
GHSR	Class A/1 (Rhodopsin-like receptors), GPCR signaling	Remarkable hypermethylation at the promoter region and first exon of the gene was detected; abnormal methylation was able to distinguish with high sensitivity and specificity malignant from normal cells; GHSR hypermethylation was reported to be identified even in early disease stages	[143]	
CLL: chronic lymphocytic leukemia, Ref.: reference, PLD1: phospholipase D1, DLC1: deleted in liver cancer 1, S1PR4: sphingosine 1-phosphate receptor 4, ET-1: endothelin 1, GHSR: growth hormone secretagogue receptor type 1, GPCR: G protein-coupled receptor, NF-kB: nuclear factor kappa-beta, IGVH: immunoglobulin variable heavy chain gene.

Table 15 Class I MHC-mediated antigen processing.

Gene names	Related pathway	Findings in CLL	Ref.	
VHL	Class I MHC-mediated antigen processing and presentation	Methylated promoter status was reported in IGVH-unmutated CLL	[14, 144]	
UBE2R2	Class I MHC-mediated antigen metabolism of proteins	Methylation levels in specific CpG sites independently predicted time to treatment with some of them being located in the gene body	[29]	
CLL: chronic lymphocytic leukemia, Ref.: reference, MHC: major histocompatibility complex, VHL: von Hippel–Lindau, UBE2R2: ubiquitin conjugating enzyme E2 R2, IGVH: immunoglobulin variable heavy chain gene.

Table 16 ESR-mediated signaling.

Gene names	Related pathway	Findings in CLL	Ref.	
MYB	Gene expression (transcription) ESR-mediated signaling, PI3K-Akt signaling, RNA polymerase I promoter opening	Methylated promoter status in IGVH-mutated cases	[14, 145]	
CHD1	ESR-mediated signaling chromatin regulation	Hypermethylated gene promoter reported in CLL samples	[102, 103]	
ESR1	PI5P, PP2A, and IER3 pathways, PI3K/Akt signaling, ESR-mediated signaling	ESR1 expression was amplified in 15% of the samples examined with copy number losses frequency ranging between 1 and 10%; ESR1 promoter region was methylated in one out of ten CLL samples controlled; in normal B cells, gene promoter was completely unmethylated	[51, 146–148]	
CLL: chronic lymphocytic leukemia, Ref.: reference, ESR1: estrogen receptor 1, MYB: myeloblastosis, CHD1: chromodomain helicase-DNA-binding protein 1, PI3K-Akt: phosphatidylinositol-3 kinase—protein kinase B, PI5P: phosphatidylinositol 5 phosphate, PP2A: protein phosphatase 2A, IER3: immediate early response 3, IGVH: immunoglobulin variable heavy chain gene.

Table 17 Angiogenesis/erythropoiesis.

Gene names	Related pathway	Findings in CLL	Ref.	
SERPINB5	TAp63 isoforms transcription angiogenesis	Methylated gene body was described in IGVH-unmutated cases	[26, 149]	
THBS1	Involved in platelet aggregation, angiogenesis, and tumorigenesis gene expression (transcription). Reactive oxygen species signaling. Nitrous oxide signaling	THBS1 promoter methylation was detected in 50% of the samples while in normal samples, gene promoters were mainly unmethylated	[51, 150, 151]	
TJP1	Immune cell transmigration VCAM-1/CD106 signaling gene expression (transcription); MAGuK tumor suppressor pathway	TJP1expression was reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 152]	
CLL: chronic lymphocytic leukemia, Ref.: reference, SERPINB5: serine protease inhibitor B5, THBS1: thrombospondin-1, TJP1: tight junction protein 1, Tap63: tumor protein P63, VCAM-1: vascular cell adhesion protein 1, CD106: cluster of differentiation 106, MAGuK: membrane-associated guanylate kinases, IGVH: immunoglobulin variable heavy chain gene.

Table 18 SLIT/ROBO signaling and nervous system development.

Gene names	Related pathway	Findings in CLL	Ref.	
SLIT2	Nervous system development; regulation of SLIT/ROBO and VEGF signaling pathways	Frequent promoter methylation was reported in high-risk CLL cases	[98, 153, 154]	
ROBO 1	Nervous system development, SLIT/ROBO signaling pathways	The expression of ROBO1 was significantly lower compared to healthy control samples; when DNA sequencing of the promoter region was performed, in most CLL samples, a higher level of methylation than the healthy individuals was identified	[155]	
ID4	Signaling by NTRKs nuclear events (kinase and transcription factor activation)	Shortened patient survival is associated with high levels of promoter; methylation ID4 promoter methylation is generally methylated in varying levels in CLL cells; ID4 mRNA and protein expression are both silenced in CLL cells, a phenomenon independent of ID4 promoter methylation status	[156–158]	
PTPRO	Signaling by the NTRKs PAK pathway	PTPRO gene promoter was methylated and expression was suppressed compared to normal B cells, with overall expression of PTPRO being lower in CLL lymphocytes than in normal samples	[51, 159–161]	
CLL: chronic lymphocytic leukemia, Ref.: reference, SLIT2: slit glycoprotein 2, ROBO1: roundabout receptor 1, ID4: inhibitor of differentiation 4, PTPRO: protein tyrosine phosphatase type O, SLIT/ROBO: slit glycoprotein/roundabout receptor, VEGF: vascular endothelial growth factor, NTRK: neurotrophic tyrosine receptor kinase, PAK: p21 activated kinase, IGVH: immunoglobulin variable heavy chain gene.

Table 19 Drug uptake mechanisms and sensitivity.

Gene names	Related pathway	Findings in CLL	Ref.	
SLC22A18	Drug sensitivity cellular metabolism and growth	Unmethylated gene body status was reported in IGVH-unmutated samples	[26, 162]	
SLCO3A1	Transport of inorganic cations/anions and amino acids/oligopeptides and transport of vitamins, nucleosides, and related molecules, drug uptake mechanisms	Differentially methylated regions of the SLCO3A gene have been associated with survival features in CLL cohorts where the hypermethylated status was linked to inferior post-treatment survival	[66]	
CLL: chronic lymphocytic leukemia, Ref.: reference, SLC22A18: solute carrier family 22, member 18, SLCO3A1: solute carrier organic anion transporter family member 3A1, IGVH: immunoglobulin variable heavy chain gene.

Table 20 Various other genes investigated in CLL.

Gene names	Related pathway	Findings in CLL	Ref.	
LPL	Statin inhibition of cholesterol production; familial hyperlipidemia type 1 pathways	Prognostic marker in CLL gene promoter methylation was associated with IGVH-mutated cases and longer time to treatment	[14, 163, 164]	
ABI3	Possible interaction with p21activated kinase inhibits ectopic metastasis of tumor cells	Gene promoter and gene body were frequently methylated in IGVH-unmutated CLL	[14, 26, 165]	
CRY1	Melatonin metabolism	Higher mRNA expression was detected in the IGVH-unmutated subgroup; treatment initiation was significantly more frequent among patients with high expression of CRY1; high expression was significantly associated with shorter intervals to first treatment	[98, 153, 154]	
SCGB2A1	Androgen receptor signaling pathway	Methylated gene body status was reported in IGVH-unmutated cases	[26, 166]	
GATA5	Cooperative activation of the intestinal lactase-phlorizin hydrolase promoter response to elevated platelet cytosolic Ca2+	GATA 5 promoter hypermethylation was detected in 35.1% of the cases	[51, 167]	
DNTT	MYC transcriptional repression DNA-PK pathway	Methylated DNTT gene body was described in IGVH-mutated samples	[26, 168, 169]	
SHANK1	Protein-protein interactions at synapses; transmission across chemical synapses	A specific CpG region of the SHANK1 body (hg19) was reported to be hypermethylated when compared to control sample methylation in the same. CpG was detectable in blood samples collected years before CLL diagnosis	[170]	
SYN2	Neurotransmitter release cycle; transmission across chemical synapses	SYN2 expression was demonstrated to be reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 171]	
CLL: chronic lymphocytic leukemia, Ref.: reference, LPL: lipoprotein lipase, ABI3: Abelson interactor family member 3, CRY1: cryptochrome 1, SCGB2A1: secretoglobin family 2A member 1, GATA5: GATA-binding protein 5, DNTT: DNA nucleotidylexotransferase, SHANK1: SH3 and multiple ankyrin repeat domain 1, SYN2: synapsin II, MYC: MYC proto-oncogene, DNA-PK: DNA-dependent protein kinase, IGVH: immunoglobulin variable heavy chain gene.

Table 21 Various other genes were investigated in CLL (cont.).

Gene names	Related pathway	Findings in CLL	Ref.	
GAB2	Insulin receptor signaling and FLT3 signaling	Genome-wide methylation profiling identified the GAB2 gene body to be differentially methylated	[130]	
OSBPL1A	Synthesis of bile acids and bile salts metabolism	OSBPL1A expression was reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 172]	
IL1B	MIF-mediated glucocorticoid regulation	Methylation levels in specific CpG sites independently predicted time to treatment with some of them being located in the gene body	[29]	
UBC	Regulation of activated PAK-2, MyD88-dependent cascade	Genome-wide methylation profiling identified UBC gene body to be differentially methylated	[130]	
IGSF4/TSLC1	Involved in cell adhesion and metastatic potential, MAGuK tumor suppressor pathway and regulation of CDH11	The frequency of gene promoter hypermethylation reached 62.2% of the samples studied methylated status of IGSF4 promoter has been reported in IGVH-unmutated cells	[51, 173–175]	
GPX3	Glutathione conjugation cellular responses to stimuli	Methylated gene body status was documented in IGVH-unmutated cases	[26, 176]	
FHL2	PPARA activates gene expression repressive role in beta-chain gene expression	Methylated FHL2 gene body was reported in IGVH-unmutated cases	[26, 177, 178]	
CLL: chronic lymphocytic leukemia, Ref.: reference, GAB2: growth factor receptor-bounding protein 2-associated binder 2, OSBPL1A: oxysterol-binding protein like 1A, IL1B: interleukin1B, UBC: induction of ubiquitin C, IGSF4/TSLC1: immunoglobulin superfamily member 4/tumor suppressor in lung cancer, GPX3: plasma glutathione peroxidase, FHL2: 4-and-a-half LIM domain protein 2, FLT3: FMS‐like tyrosine kinase 3, MIF: macrophage migration inhibitory factor, PAK-2: p21 activated kinase 2, MyD88: myeloid differentiation primary response protein 88, MAGuK: membrane-associated guanylate kinase, CDH11: cadherin 11, PPARA: peroxisome proliferator-activated receptor alpha, IGVH: immunoglobulin variable heavy chain gene.

Table 22 Various other genes were investigated in CLL (cont.).

Gene names	Related pathway	Findings in CLL	Ref.	
REPS1	Vesicle-mediated transport and clathrin-mediated endocytosis	Methylation levels in specific CpG sites independently predicted time to treatment with some of them being located in the gene body	[29]	
ATP9B	Ion channel transport and cardiac conduction	Methylation levels in specific CpG sites independently predicted time to treatment with some of them being located in the gene body	[29]	
GRB2	Downstream signaling of activated FGFR2 and prolactin signaling	Genome-wide methylation profiling identified GRB2 gene body to be differentially methylated	[130]	
DLEU7	 	Analysis did not detect any specific mutations in DLEU7, but DLEU7 expression was absent in CLL cells; methylation of a CpG island in the promoter region of DLEU7 was identified as a possible explanation for the absence of DLEU7 expression, with the promoter reported to be methylated in most of the CLL samples	[179]	
ADAMTS17	Metabolism of proteins immune cell transmigration, VCAM-1/CD106 signaling, gene expression (transcription). MAGuK tumor suppressor pathway	ADAMTS17 expression was reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 180]	
KCNG2	Integration of energy metabolism potassium channels	KCNG2 expression was reported to be reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 181]	
ME3	Respiratory electron transport ATP synthesis TCA cycle	ME3 expression was reported to be reduced in patients with hypermethylated promoter regions and hypomethylated body regions	[37, 182]	
CLL: chronic lymphocytic leukemia, Ref.: reference, REPS1: RalA-binding protein-associated Eps domain-containing 1, ATP9B: ATPase phospholipid transporting 9B, GRB2: growth factor receptor-bounding protein 2, DLEU7: deleted in lymphocytic leukemia 7, ADAMTS17: a disintegrin and metalloproteinase with thrombospondin motifs 17, KCNG2: potassium voltage-gated channel modifier subfamily G member 2, ME3: malic enzyme 3, FGFR2: fibroblast growth factor receptor 2, VCAM-1: vascular cell adhesion protein 1, CD106: cluster of differentiation 106, MAGuK: membrane-associated guanylate kinase, ATP: adenosine triphosphate, TCA: tricarboxylic acid.

Table 23 Noncoding RNAs.non

Gene names	Related pathway	Findings in CLL	Ref.	
CRNDE	Involved in the expression of genes associated to metabolism and in neoplasms biology inversely regulated by insulin and insulin-like growth factors	CRNDE expression was downregulated and the methylation level of CRNDE promoter was higher compared to normal B cells; after exposure to demethylating agents, an increase of CRNDE expression levels was reported	[183]	
NCRMS	 	Methylated gene body status correlated with IGVH-mutated status	[26, 184]	
BM742401	 	Overexpression of BM742401 in CLL led to interruption of cellular proliferation and increased apoptosis; in CLL cell lines, BM742401 promoter was methylated in 57.1% of the samples compared to normal controls where the promoter was unmethylated; methylation of BM742401 negatively associated with its expression and 5-aza-2′-deoxycytidine exposure caused promoter demethylation with consequent activation of BM742401 expression; methylation of BM742401 correlated with higher Rai stage among in the subgroup of CLL patients with standard-risk cytogenetic features	[185]	
CLLU1	 	mRNA expression level predicted time to treatment and survival; methylated gene promoter correlated with decreased expression and IGVH-mutated cases	[14, 186]	
AC012065.7	Positive expression relationship with nearby GDF7 gene. GDF7 protein is involved in growth, repair, and embryonic development	Gene promoter methylation levels reported to be inversely correlated to gene expression levels and survival analysis demonstrated that hypomethylated gene promoter status of AC012065.7 was associated with an inferior prognosis	[187]	
CLL: chronic lymphocytic leukemia, Ref.: reference, CLLU1: chronic lymphocytic leukemia upregulated 1, NCRMS: noncoding RNA in rhabdomyosarcoma, BM742401: GATA6 antisense RNA 1, CRNDE: colorectal neoplasia differentially expressed, GDF7: growth differentiation factor 7, IGVH: immunoglobulin variable heavy chain gene.
==== Refs
1 Siegel R. L. Miller K. D. Wagle N. S. Jemal AL Cancer statistics CA: A Cancer Journal for Clinicians 2023 73 1 17 48 10.3322/caac.21763 36633525
2 Hernández J. A. Land K. J. McKenna R. W. Leukemia, myeloma, and other lymphoreticular neoplasms Cancer 1995 75 1 381 10.1002/1097-0142(19950101)75:1+<381::AID-CNCR2820751320>3.0.CO;2-B 7804962
3 Smith A. Howell D. Patmore R. Jack A. Roman E. Incidence of haematological malignancy by subtype: a report from the haematological malignancy research network British Journal of Cancer 2011 105 11 1684 1692 10.1038/bjc.2011.450 2-s2.0-81955165195 22045184
4 Hallek M. Cheson B. D. Catovsky D. IwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL Blood 2018 131 25 2745 2760 10.1182/blood-2017-09-806398 2-s2.0-85049186980 29540348
5 Grubor V. Krasnitz A. Troge J. E. Novel genomic alterations and clonal evolution in chronic lymphocytic leukemia revealed by representational oligonucleotide microarray analysis (ROMA) Blood 2009 113 6 1294 1303 10.1182/blood-2008-05-158865 2-s2.0-60849118132 18922857
6 Landau D. A. Tausch E. Taylor-Weiner A. N. Mutations driving CLL and their evolution in progression and relapse Nature 2015 526 7574 525 530 10.1038/nature15395 2-s2.0-84945302209 26466571
7 Nadeu F. Delgado J. Royo C. Clinical impact of clonal and subclonal TP53, SF3B1BIRC3, NOTCH1, and ATM mutations in chronic lymphocytic leukemia Blood 2016 127 17 2122 2130 10.1182/blood-2015-07-659144 2-s2.0-85011375984 26837699
8 Wu C. J. CLL clonal heterogeneity: an ecology of competing subpopulations Blood 2012 120 20 4117 4118 10.1182/blood-2012-09-452805 2-s2.0-84869805516 23160186
9 Minden M. D. V Übelhart R. Schneider D. Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling Nature 2012 489 7415 309 312 10.1038/nature11309 2-s2.0-84866152172 22885698
10 Woyach J. A. Johnson A. J. Byrd J. C. The B-cell receptor signaling pathway as a therapeutic target in CLL Blood 2012 120 6 1175 1184 10.1182/blood-2012-02-362624 2-s2.0-84865176364 22715122
11 Vardi A. Agathangelidis A. Sutton L. A. Ghia P. Rosenquist R. Stamatopoulos K. Immunogenetic studies of chronic lymphocytic leukemia: revelations and speculations about ontogeny and clinical evolution Cancer Research 2014 74 16 4211 4216 10.1158/0008-5472.CAN-14-0630 2-s2.0-84905980544 25074616
12 Wajed S. A. Laird P. W. DeMeester T. R. DNA methylation: an alternative pathway to cancer Annals of Surgery 2001 234 1 10 20 10.1097/00000658-200107000-00003 2-s2.0-0034929515 11420478
13 Zhang C. Zhao H. Li J. The identification of specific methylation patterns across different cancers PLoS One 2015 10 3 e0120361 10.1371/journal.pone.0120361 2-s2.0-84924942532
14 Cahill N. Bergh A. C. Kanduri M. 450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments Leukemia 2013 27 1 150 158 10.1038/leu.2012.245 2-s2.0-84873570131 22922567
15 Wahlfors J. Hiltunen H. Heinonen K. Hämäläinen E. Alhonen L. Jänne J. Genomic hypomethylation in human chronic lymphocytic leukemia Blood 1992 80 8 2074 2080 10.1182/blood.V80.8.2074.2074 1382719
16 Blecua P. Martinez-Verbo L. Esteller M. The DNA methylation landscape of hematological malignancies: an update Molecular Oncology 2020 14 8 1616 1639 10.1002/1878-0261.12744 32526054
17 Fabris S. Bollati V. Agnelli L. Biological and clinical relevance of quantitative global methylation of repetitive DNA sequences in chronic lymphocytic leukemia Epigenetics 2011 6 2 188 194 10.4161/epi.6.2.13528 2-s2.0-79951499200 20930513
18 Kulis M. Heath S. Bibikova M. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia Nature Genetics 2012 44 11 1236 1242 10.1038/ng.2443 2-s2.0-84868198427 23064414
19 Rush L. J. Raval A. Funchain P. Epigenetic profiling in chronic lymphocytic leukemia reveals novel methylation targets Cancer Research 2004 64 7 2424 2433 10.1158/0008-5472.CAN-03-2870 2-s2.0-11144356462 15059895
20 Oakes C. C. Seifert M. Assenov Y. DNA methylation dynamics during B cell maturation underlie a continuum of disease phenotypes in chronic lymphocytic leukemia Nature Genetics 2016 48 3 253 264 10.1038/ng.3488 2-s2.0-84959519942 26780610
21 Rozovski U. Keating M. Estrov Z. The significance of spliceosome mutations in chronic lymphocytic leukemia Leukemia and Lymphoma 2013 54 7 1364 1366 10.3109/10428194.2012.742528 2-s2.0-84877926730 23270583
22 Hanada M. Delia D. Aiello A. Stadtmauer E. Reed J. C. bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia Blood 1993 82 6 1820 1828 10.1182/blood.V82.6.1820.1820 8104532
23 Kantharidis P. El-Osta A. deSilva M. Altered methylation of the human MDR1 promoter is associated with acquired multidrug resistance Clinical Cancer Research 1997 3 11 2025 2032 9815593
24 Yuille M. R. Condie A. Stone E. M. TCL1 is activated by chromosomal rearrangement or by hypomethylation Genes, Chromosomes and Cancer 2001 30 4 336 341 10.1002/gcc.1099 2-s2.0-0035100284 11241786
25 Pei L. Choi J. H. Liu J. Genome-wide DNA methylation analysis reveals novel epigenetic changes in chronic lymphocytic leukemia Epigenetics 2012 7 6 567 578 10.4161/epi.20237 2-s2.0-84861922114 22534504
26 Kanduri M. Cahill N. Göransson H. Differential genome-wide array-based methylation profiles in prognostic subsets of chronic lymphocytic leukemia Blood 2010 115 2 296 305 10.1182/blood-2009-07-232868 2-s2.0-75649133610 19897574
27 Baer C. Claus R. Frenzel L. P. Extensive promoter DNA hypermethylation and hypomethylation is associated with aberrant microRNA expression in chronic lymphocytic leukemia Cancer Research 2012 72 15 3775 3785 10.1158/0008-5472.can-12-0803 2-s2.0-84864856010 22710432
28 Queirós A. C. Villamor N. Clot G. A B-cell epigenetic signature defines three biologic subgroups of chronic lymphocytic leukemia with clinical impact Leukemia 2015 29 3 598 605 10.1038/leu.2014.252 2-s2.0-84924540077 25151957
29 Hussmann D. Starnawska A. Kristensen L. IGHV-associated methylation signatures more accurately predict clinical outcomes of chronic lymphocytic leukemia patients than IGHV mutation load Haematologica 2021 107 4 877 886 10.3324/haematol.2021.278477
30 Bechter O. E. Eisterer W. Dlaska M. Kühr T. Thaler J. CpG island methylation of the hTERT promoter is associated with lower telomerase activity in B-cell lymphocytic leukemia Experimental Hematology 2002 30 1 26 33 10.1016/S0301-472X(01)00760-3 2-s2.0-0036142690 11823034
31 Martel V. Guerci A. Humbert J. C. De novo methylation of tumour suppressor genes CDKN2A and CDKN2B is a rare finding in B-cell chronic lymphocytic leukaemia British Journal of Haematology 1997 99 2 320 324 10.1046/j.1365-2141.1997.3953209.x 2-s2.0-0030726251 9375748
32 Seeliger B. Wilop S. Osieka R. Galm O. Jost E. CpG island methylation patterns in chronic lymphocytic leukemia Leukemia and Lymphoma 2009 50 3 419 426 10.1080/10428190902756594 2-s2.0-67650912362 19347729
33 Papageorgiou S. G. Lambropoulos S. Pappa V. Hypermethylation of the p15INK4B gene promoter in B‐chronic lymphocytic leukemia American Journal of Hematology 2007 82 9 824 825 10.1002/ajh.20914 2-s2.0-35748963256 17546638
34 Herman J. G. Civin C. I. Issa J. P. Collector M. I. Sharkis S. J. Baylin S. B. Distinct patterns of inactivation of p15INK4B and p16INK4A characterize the major types of hematological malignancies Cancer Research 1997 57 5 837 841 9041182
35 Filarsky K. Garding A. Becker N. Krüppel-like factor 4 (KLF4) inactivation in chronic lymphocytic leukemia correlates with promoter DNA-methylation and can be reversed by inhibition of NOTCH signaling Haematologica 2016 101 6 e249 e253 10.3324/haematol.2015.138172 2-s2.0-84971553902 27081174
36 Forsterová K. Votavová H. Schwarz J. Karban J. Stuka C. Trněný M. Advanced rai stage in patients with chronic lymphocytic leukaemia correlates with simultaneous hypermethylation of plural tumour suppressor genes Folia Biologica 2010 56 4 158 164 20974048
37 Zhang Q. Gao Y. Lin S. Genome-wide DNA methylation profiling in chronic lymphocytic leukaemia Frontiers in Genetics 2022 13 1056043 10.3389/fgene.2022.1056043
38 Rogowski K. van Dijk J. Magiera M. M. A family of protein-deglutamylating enzymes associated with neurodegeneration Cell 2010 143 4 564 578 10.1016/j.cell.2010.10.014 2-s2.0-78149486157 21074048
39 Chatzidavid S. Kontandreopoulou C. N. Diamantopoulos P. The clinical and prognostic significance of ribonucleotide reductase subunits RRM1 and RRM2 mRNA levels in patients with chronic lymphocytic leukemia Clinical Hematology International 2023 5 2-3 92 100 10.1007/s44228-023-00033-x 36811764
40 Rankin S. Complex elaboration: making sense of meiotic cohesin dynamics FEBS Journal 2015 282 13 2426 2443 10.1111/febs.13301 2-s2.0-84934297908 25895170
41 Gelot C. Guirouilh-Barbat J. Le Guen T. The cohesin complex prevents the end joining of distant DNA double-strand ends Molecular Cell 2016 61 1 15 26 10.1016/j.molcel.2015.11.002 2-s2.0-84953636418 26687679
42 Solomon D. A. Kim J. S. Waldman T. Cohesin gene mutations in tumorigenesis: from discovery to clinical significance BMB Reports 2014 47 6 299 310 10.5483/bmbrep.2014.47.6.092 2-s2.0-84903590872 24856830
43 Thota S. Viny A. D. Makishima H. Genetic alterations of the cohesin complex genes in myeloid malignancies Blood 2014 124 11 1790 1798 10.1182/blood-2014-04-567057 2-s2.0-84908611207 25006131
44 Mullenders J. Aranda-Orgilles B. Lhoumaud P. Cohesin loss alters adult hematopoietic stem cell homeostasis, leading to myeloproliferative neoplasms Journal of Experimental Medicine 2015 212 11 1833 1850 10.1084/jem.20151323 2-s2.0-84952061852 26438359
45 Ioannidou A. Zachaki S. Karakosta M. Daraki A. Roussou P. Manola K. N. Cohesin RAD21 Gene Promoter Methylation in Patients with Chronic Lymphocytic Leukemia Cytogenetic and Genome Research 2018 154 3 126 131 10.1159/000487868 2-s2.0-85044524426 29587287
46 Esteller M. Hamilton S. R. Burger P. C. Baylin S. B. Herman J. G. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia Cancer Research 1999 59 4 793 797 10029064
47 Lenz G. Hutter G. Hiddemann W. Dreyling M. Promoter methylation and expression of DNA repair genes hMLH1 and MGMT in acute myeloid leukemia Annals of Hematology 2004 83 10 628 633 10.1007/s00277-004-0925-0 2-s2.0-4844221344 15309527
48 Rossi D. Capello D. Gloghini A. Aberrant promoter methylation of multiple genes throughout the clinico-pathologic spectrum of B-cell neoplasia Haematologica 2004 89 2 154 164 15003890
49 Sobieszkoda D. Czech J. Gablo N. MGMT promoter methylation as a potential prognostic marker for acute leukemia Archives of Medical Science 2017 6 1433 1441 10.5114/aoms.2017.71067 2-s2.0-85032703589
50 Fülöp Z. Csernus B. Tímár B. Szepesi Á Matolcsy A. Microsatellite instability and hMLH1 promoter hypermethylation in Richter’s transformation of chronic lymphocytic leukemia Leukemia 2003 17 2 411 415 10.1038/sj.leu.2402792 2-s2.0-0037330832 12592341
51 Cosialls A. M. Santidrián A. F. Coll-Mulet L. Epigenetic profile in chronic lymphocytic leukemia using methylation-specific multiplex ligation-dependent probe amplification Epigenomics 2012 4 5 491 501 10.2217/epi.12.40 2-s2.0-84868560560 23130831
52 Bahari G. Hashemi M. Naderi M. Sadeghi-Bojd S. Taheri M. FHIT promoter DNA methylation and expression analysis in childhood acute lymphoblastic leukemia Oncology Letters 2017 14 4 5034 5038 10.3892/ol.2017.6796 2-s2.0-85028911487 29085517
53 Takeuchi S. Matsushita M. Zimmermann M. Clinical significance of aberrant DNA methylation in childhood acute lymphoblastic leukemia Leukemia Research 2011 35 10 1345 1349 10.1016/j.leukres.2011.04.015 2-s2.0-80052077665 21592569
54 Cui J. Li G. Yin J. GSTP1 and cancer: expression, methylation, polymorphisms and signaling (Review) International Journal of Oncology 2020 56 4 867 878 10.3892/ijo.2020.4979 32319549
55 Paixão V. A. Vidal D. O. Caballero O. L. Hypermethylation of CpG island in the promoter region of CALCA in acute lymphoblastic leukemia with central nervous system (CNS) infiltration correlates with poorer prognosis Leukemia Research 2006 30 7 891 894 10.1016/j.leukres.2005.11.016 2-s2.0-33744516096 16712930
56 Yuille M. Condie A. Hudson C. Relationship between glutathione S-transferase M1, T1, and P1 polymorphisms and chronic lymphocytic leukemia Blood 2002 99 11 4216 4218 10.1182/blood.V99.11.4216 2-s2.0-0036624745 12010828
57 Rosenthal F. Feijs K. L. H. Frugier E. Macrodomain-containing proteins are new mono-ADP-ribosylhydrolases Nature Structural & Molecular Biology 2013 20 4 502 507 10.1038/nsmb.2521 2-s2.0-84876167387
58 Bar-Yehuda S. Stemmer S. M. Madi L. The A3 adenosine receptor agonist CF102 induces apoptosis of hepatocellular carcinoma via de-regulation of the Wnt and NF-kappaB signal transduction pathways International Journal of Oncology 2008 33 2 287 295 10.3892/ijo_00000008 2-s2.0-48749128664 18636149
59 Palma M. Gentilcore G. Heimersson K. T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers Haematologica 2017 102 3 562 572 10.3324/haematol.2016.151100 2-s2.0-85014496887 27927767
60 Van Vlierberghe P. Beverloo H. B. Buijs-Gladdines J. Monoallelic or biallelic LMO2 expression in relation to the LMO2 rearrangement status in pediatric T-cell acute lymphoblastic leukemia Leukemia 2008 22 7 1434 1437 10.1038/sj.leu.2405063 2-s2.0-47549109069 18079736
61 Zhang M. Swanson P. C. Swanson PC: V(D)J recombinase binding and cleavage of cryptic recombination signal sequences identified from lymphoid malignancies Journal of Biological Chemistry 2008 283 11 6717 6727 10.1074/jbc.M710301200 2-s2.0-43749118207 18187418
62 Natkunam Y. Zhao S. Mason D. Y. The oncoprotein LMO2 is expressed in normal germinal center B cells and in human B-cell lymphomas Blood 2007 109 4 1636 1642 10.1182/blood-2006-08-039024 2-s2.0-33846935905 17038524
63 di Martino O. Welch J. S. Retinoic acid receptors in acute myeloid leukemia therapy Cancers 2019 11 12 p. 1915 10.3390/cancers11121915
64 Maiti G. P. Sinha S. Mahmud H. SIRT3 overexpression and epigenetic silencing of catalase regulate ROS accumulation in CLL cells activating AXL signaling axis Blood Cancer Journal 2021 11 5 p. 93 10.1038/s41408-021-00484-6
65 Xiang Z. Yuan W. Luo N. A novel human zinc finger protein ZNF540 interacts with MVP and inhibits transcriptional activities of the ERK signal pathway Biochemical and Biophysical Research Communications 2006 347 1 288 296 10.1016/j.bbrc.2006.06.076 2-s2.0-33745812073 16815308
66 Barrow T. M. Nakjang S. Lafta F. Epigenome-wide analysis reveals functional modulators of drug sensitivity and posttreatment survival in chronic lymphocytic leukaemia British Journal of Cancer 2021 124 2 474 483 10.1038/s41416-020-01117-8 33082556
67 Strathdee G. Sim A. Parker A. Oscier D. Brown R. Promoter hypermethylation silences expression of the HoxA4 gene and correlates with IgVh mutational status in CLL Leukemia 2006 20 7 1326 1329 10.1038/sj.leu.2404254 2-s2.0-33745198269 16688227
68 Irving L. Mainou-Fowler T. Parker A. Ibbotson R. E. Oscier D. G. Strathdee G. Methylation markers identify high risk patients inIGHVmutated chronic lymphocytic leukemia Epigenetics 2011 6 3 300 306 10.4161/epi.6.3.14038 2-s2.0-79952389811 21051931
69 Kopparapu P. K. Abdelrazak Morsy M. Kanduri C. Kanduri M. Gene-body hypermethylation controlled cryptic promoter and miR26A1-dependent EZH2 regulation of TET1 gene activity in chronic lymphocytic leukemia Oncotarget 2017 8 44 77595 77608 10.18632/oncotarget.20668 2-s2.0-85030320276 29100411
70 Attia H. R. Ibrahim M. H. El-Aziz S. H. A. ITGA4 gene methylation status in chronic lymphocytic leukemia Future Science OA 2020 6 7 p. 583 10.2144/fsoa-2020-0034
71 Jin Q. Chen H. Luo A. Ding F. Liu Z. S100A14 stimulates cell proliferation and induces cell apoptosis at different concentrations via the receptor for advanced glycation end products (RAGE) PLoS One 2016 11 1 e0147881 10.1371/journal.pone.0147881 2-s2.0-84958212504
72 Chen H. Yu D. Luo A. Functional role of S100A14 genetic variants and their association with esophageal squamous cell carcinoma Cancer Research 2009 69 8 3451 3457 10.1158/0008-5472.CAN-08-4231 2-s2.0-65949087478 19351828
73 Contente A. Dittmer A. Koch M. C. Roth J. Dobbelstein M. A polymorphic microsatellite that mediates induction of PIG3 by p53 Nature Genetics 2002 30 3 315 320 10.1038/ng836 2-s2.0-0036510121 11919562
74 Voltan R. Secchiero P. Corallini F. Zauli G. Selective induction of TP53I3/p53-inducible gene 3 (PIG3) in myeloid leukemic cells, but not in normal cells by Nutlin-3 Molecular Carcinogenesis 2014 53 6 498 504 10.1002/mc.21985 2-s2.0-84899979037 23192887
75 Saeed W. H. Eissa A. A. Al-Doski A. A. Impact of TP53 gene promoter methylation on chronic lymphocytic leukemia pathogenesis and progression Journal of Blood Medicine 2019 10 399 404 10.2147/JBM.S221707 31819692
76 Flatt P. M. Polyak K. Tang L. J. p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest Cancer Letters 2000 156 1 63 72 10.1016/s0304-3835(00)00441-9 2-s2.0-0034256962 10840161
77 Boominathan L. Some facts and thoughts: p73 as a tumor suppressor gene in the network of tumor suppressors Molecular Cancer 2007 6 1 p. 27 10.1186/1476-4598-6-27 2-s2.0-34247371414
78 Novak U. Grob T. J. Baskaynak G. Overexpression of the p73 gene is a novel finding in high-risk B-cell chronic lymphocytic leukemia Annals of Oncology 2001 12 7 981 986 10.1023/A:1011153206003 2-s2.0-0034899043 11521806
79 Corn P. G. Kuerbitz S. J. van Noesel M. M. Transcriptional silencing of the p73 gene in acute lymphoblastic leukemia and Burkitt’s lymphoma is associated with 5’ CpG island methylation Cancer Research 1999 59 14 3352 3356 10416592
80 Papakonstantinou N. Ntoufa S. Tsagiopoulou M. Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia International Journal of Cancer 2019 144 11 2695 2706 10.1002/ijc.31999 2-s2.0-85060151431 30447004
81 Raneros A. B. Minguela A. Rodriguez R. M. Increasing TIMP3 expression by hypomethylating agents diminishes soluble MICA, MICB, and ULBP2 shedding in acute myeloid leukemia, facilitating NK cell-mediated immune recognition Oncotarget 2017 8 19 31959 31976 10.18632/oncotarget.16657 2-s2.0-85019075572 28404876
82 Wang D. D. Xu W. X. Chen W. Q. Identification of TIMP2 as a prognostic biomarker and its correlation with yumor immune microenvironment: a comprehensive pan-cancer analysis JAMA Oncology 2022 59 14 3352 3356 10.1155/2022/9133636
83 Troeger A. Gudowius S. Escherich G. High nerve growth factor receptor (p75NTR) expression is a favourable prognostic factor in paediatric B cell precursor acute lymphoblastic leukaemia British Journal of Haematology 2007 139 3 450 457 10.1111/j.1365-2141.2007.06818.x 2-s2.0-34848906811 17910636
84 Hutterer E. Asslaber D. Caldana C. CD18 (ITGB2) expression in chronic lymphocytic leukaemia is regulated by DNA methylation-dependent and independent mechanisms British Journal of Haematology 2015 169 2 286 289 10.1111/bjh.13188 2-s2.0-84926334027 25322676
85 Rinaldi A. Mensah A. A. Kwee I. Promoter methylation patterns in Richter syndrome affect stem cell maintenance and cell cycle regulation and differ from de novo diffuse large B-cell lymphoma British Journal of Haematology 2013 163 2 194 204 10.1111/bjh.12515 2-s2.0-84884988160 23961875
86 Rivas S. Marín A. Samtani S. González-Feliú E. Armisén R. MET signaling pathways, resistance mechanisms, and opportunities for target therapies International Journal of Molecular Sciences 2022 23 22 13898 10.3390/ijms232213898
87 Raval A. Lucas D. M. Matkovic J. J. TWIST2 demonstrates differential methylation in immunoglobulin variable heavy chain mutated and unmutated chronic lymphocytic leukemia Journal of Clinical Oncology 2005 23 17 3877 3885 10.1200/JCO.2005.02.196 2-s2.0-21244503530 15809452
88 Barrow T. M. Wong Doo N. Milne R. L. Analysis of retrotransposon subfamily DNA methylation reveals novel early epigenetic changes in chronic lymphocytic leukemia Haematologica 2020 106 1 98 110 10.3324/haematol.2019.228478
89 Buggins A. G. S. Pepper C. J. The role of Bcl-2 family proteins in chronic lymphocytic leukaemia Leukemia Research 2010 34 7 837 842 10.1016/j.leukres.2010.03.011 2-s2.0-77952952903 20359747
90 Haudenschild D. R. Curtiss S. B. Moseley T. A. Reddi A. H. Generation of interleukin-17 receptor-like protein (IL-17RL) in prostate by alternative splicing of RNA The Prostate 2006 66 12 1268 1274 10.1002/pros.20422 2-s2.0-33748337902 16688746
91 Giannopoulos K. Li L. Bojarska-Junak A. Expression of RHAMM/CD168 and other tumor-associated antigens in patients with B-cell chronic lymphocytic leukemia International Journal of Oncology 2006 29 1 95 103 10.3892/ijo.29.1.95 16773189
92 Rosenfeld C. Cheever M. Gaiger A. WT1 in acute leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome: therapeutic potential of WT1 targeted therapies Leukemia 2003 17 7 1301 1312 10.1038/sj.leu.2402988 2-s2.0-0038780854 12835718
93 Sztrolovics R. Chen X.-N. Grover J. Roughley P. J. Korenberg J. R. Localization of the human fibromodulin gene (FMOD) to chromosome 1q32 and completion of the cDNA sequence Genomics 1994 23 3 715 717 10.1006/geno.1994.1567 2-s2.0-0028172975 7851907
94 Bashford-Rogers R. J. M. Palser A. L. Hodkinson C. Dynamic variation of CD5 surface expression levels within individual chronic lymphocytic leukemia clones Experimental Hematology 2017 46 31 37.e10 10.1016/j.exphem.2016.09.010 2-s2.0-85003810978 27693386
95 Poppova L. Pavlova S. Gonzalez B. Memory B-cell like chronic lymphocytic leukaemia is associated with specific methylation profile of WNT5A promoter and undetectable expression of WNT5A gene Epigenetics 2022 17 12 1628 1635 10.1080/15592294.2022.2050004 35333703
96 Kleer C. G. Zhang Y. Pan Q. WISP3 is a novel tumor suppressor gene of inflammatory breast cancer Oncogene 2002 21 20 3172 3180 10.1038/sj.onc.1205462 2-s2.0-85047695306 12082632
97 Gutierrez A. Jr Tschumper R. C. Wu X. LEF-1 is a prosurvival factor in chronic lymphocytic leukemia and is expressed in the preleukemic state of monoclonal B-cell lymphocytosis Blood 2010 116 16 2975 2983 10.1182/blood-2010-02-269878 2-s2.0-77958164865 20595513
98 Rani L. Mathur N. Gupta R. Genome-wide DNA methylation profiling integrated with gene expression profiling identifies PAX9 as a novel prognostic marker in chronic lymphocytic leukemia Clinical Epigenetics 2017 9 1 p. 57 10.1186/s13148-017-0356-0 2-s2.0-85019736360
99 Liu T. H. Raval A. Chen S. S. Matkovic J. J. Byrd J. C. Plass C. CpG island methylation and expression of the secreted frizzled-related protein gene family in chronic lymphocytic leukemia Cancer Research 2006 66 2 653 658 10.1158/0008-5472.can-05-3712 2-s2.0-33645564002 16423993
100 Chim C. S. Pang R. Liang R. Epigenetic dysregulation of the Wnt signalling pathway in chronic lymphocytic leukaemia Journal of Clinical Pathology 2008 61 11 1214 1219 10.1136/jcp.2008.060152 2-s2.0-56049111627 18765431
101 Moskalev E. A. Luckert K. Vorobjev I. A. Concurrent epigenetic silencing of wnt/β-catenin pathway inhibitor genes in B cell chronic lymphocytic leukaemia BMC Cancer 2012 12 1 p. 213 10.1186/1471-2407-12-213 2-s2.0-84861831963
102 Melki J. R. Vincent P. C. Brown R. D. Clark S. J. Hypermethylation of E-cadherin in leukemia Blood 2000 95 10 3208 3213 10.1182/blood.V95.10.3208 10807790
103 Berx G. Cleton‐Jansen A. M. Nollet F. E-cadherin is a tumour/invasion suppressor gene mutated in human lobular breast cancers The EMBO Journal 1995 14 24 6107 6115 10.1002/j.1460-2075.1995.tb00301.x 8557030
104 Schmidt-Wolf I. G. H. Plass C. Byrd J. C. Frevel K. Pietsch T. Waha A. Assessment of promoter methylation identifies PTCH as a putative tumor suppressor gene in human CLL Anticancer Research 2016 36 9 4515 4519 10.21873/anticanres.10998 2-s2.0-84991628640 27630290
105 Wolf C. Garding A. Filarsky K. NFATC1 activation by DNA hypomethylation in chronic lymphocytic leukemia correlates with clinical staging and can be inhibited by ibrutinib International Journal of Cancer 2018 142 2 322 333 10.1002/ijc.31057 2-s2.0-85030714662 28921505
106 Zarnack K. Eichhorn H. Kahmann R. Feldbrügge M. Pheromone-regulated target genes respond differentially to MAPK phosphorylation of transcription factor Prf1 Molecular Microbiology 2008 69 4 1041 1053 10.1111/j.1365-2958.2008.06345.x 2-s2.0-47749137818 18627457
107 Grimwade D. Du M. Q. Langabeer S. Rogers J. Solomon E. Screening for mutations of Bcl10 in leukaemia British Journal of Haematology 2000 109 3 611 615 10.1046/j.1365-2141.2000.02092.x 2-s2.0-0034086741 10886211
108 Kanazawa N. Okafuji I. Kambe N. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor- B activation: common genetic etiology with Blau syndrome Blood 2004 105 3 1195 1197 10.1182/blood-2004-07-2972 2-s2.0-19944431022 15459013
109 Ishikawa H. Barber G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling Nature 2008 455 7213 674 678 10.1038/nature07317 2-s2.0-53349178089 18724357
110 Zhang J. Xu L. G. Han K. J. Shu H. B. Identification of a ZU5 and death domain-containing inhibitor of NF-κB Journal of Biological Chemistry 2004 279 17 17819 17825 10.1074/jbc.M310737200 2-s2.0-2342425696 14769797
111 Lee C. H. Wong T. S. Chan J. Y. W. Epigenetic regulation of the X‐linked tumour suppressors <scp>BEX1</scp> and <scp>LDOC1</scp> in oral squamous cell carcinoma The Journal of Pathology 2013 230 3 298 309 10.1002/path.4173 2-s2.0-84878771970 23362108
112 Nagasaki K. Schem C. von Kaisenberg C. Leucine-zipper protein, LDOC1 inhibits NF-κB activation and sensitizes pancreatic cancer cells to apoptosis International Journal of Cancer 2003 105 4 454 458 10.1002/ijc.11122 2-s2.0-0038324141 12712434
113 Wang L. Deng W. Shi T. Ma D. URP2SF, a FERM and PH domain containing protein, regulates NF-κB and apoptosis Biochemical and Biophysical Research Communications 2008 368 4 899 906 10.1016/j.bbrc.2008.02.024 2-s2.0-40049103480 18280249
114 Chen L. Widhopf G. Huynh L. Expression of ZAP-70 is associated with increased B-cell receptor signaling in chronic lymphocytic leukemia Blood 2002 100 13 4609 4614 10.1182/blood-2002-06-1683 2-s2.0-0037114744 12393534
115 Wiestner A. Rosenwald A. Barry T. S. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile Blood 2003 101 >12 4944 4951 10.1182/blood-2002-10-3306 12595313
116 Corcoran M. Parker A. Orchard J. ZAP-70 methylation status is associated with ZAP-70 expression status in chronic lymphocytic leukemia Haematologica 2005 90 8 1078 1088 16079107
117 Chantepie S. P. Vaur D. Grunau C. ZAP-70 intron1 DNA methylation status: determination by pyrosequencing in B chronic lymphocytic leukemia Leukemia Research 2010 34 6 800 808 10.1016/j.leukres.2009.10.018 2-s2.0-77952094636 19944462
118 Claus R. Lucas D. M. Stilgenbauer S. Quantitative DNA methylation analysis identifies a single CpG dinucleotide important for ZAP-70 expression and predictive of prognosis in chronic lymphocytic leukemia Journal of Clinical Oncology 2012 30 20 2483 2491 10.1200/JCO.2011.39.3090 2-s2.0-84864071185 22564988
119 Maisonpierre P. C. Suri C. Jones P. F. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis Science 1997 277 5322 55 60 10.1126/science.277.5322.55 2-s2.0-15144358851 9204896
120 Krug S. Huth J. Göke F. Knock-down of Pdcd4 stimulates angiogenesis via upregulation of angiopoietin-2 Biochimica et Biophysica Acta (BBA) Molecular Cell Research 2012 1823 4 789 799 10.1016/j.bbamcr.2012.01.006 2-s2.0-84857425221 22289349
121 Martinelli S. Kanduri M. Maffei R. ANGPT2promoter methylation is strongly associated with gene expression and prognosis in chronic lymphocytic leukemia Epigenetics 2013 8 7 720 729 10.4161/epi.24947 2-s2.0-84879674710 23803577
122 Hojjat-Farsangi M. Jeddi-Tehrani M. Daneshmanesh A. H. Spontaneous immunity against the receptor tyrosine kinase ROR1 in patients with chronic lymphocytic leukemia PLoS One 2015 10 11 e0142310 10.1371/journal.pone.0142310 2-s2.0-84955614428
123 Raval A. Tanner S. M. Byrd J. C. Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia Cell 2007 129 5 879 890 10.1016/j.cell.2007.03.043 2-s2.0-34249314024 17540169
124 Mohamad A. Hassan R. Husin A. Johan M. F. Sulong S. Aberrant methylation of tumour suppressor gene ADAM12 in chronic lympocytic leukemia patients: application of methylation specific PCr technique Asian Pacific Journal of Cancer Prevention 2021 22 1 85 91 10.31557/APJCP.2021.22.1.85 33507683
125 Nagafuchi S. Katsuta H. Koyanagi-Katsuta R. Autoimmune regulator (AIRE) gene is expressed in human activated CD4+ T-cells and regulated by mitogen-activated protein kinase pathway Microbiology and Immunology 2006 50 12 979 987 10.1111/j.1348-0421.2006.tb03876.x 2-s2.0-33845777193 17179667
126 Okamura S. M. Oki-Idouchi C. E. Lorenzo P. S. The exchange factor and diacylglycerol receptor RasGRP3 interacts with dynein light chain 1 through its C-terminal domain Journal of Biological Chemistry 2006 281 47 36132 36139 10.1074/jbc.M605093200 2-s2.0-33845972283 17012239
127 Zheng Y. Liu H. Coughlin J. Zheng J. Li L. Stone J. C. Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells Blood 2005 105 9 3648 3654 10.1182/blood-2004-10-3916 2-s2.0-18244409902 15657177
128 Coughlin J. J. Stang S. L. Dower N. A. Stone J. C. RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor Ras signaling The Journal of Immunology 2005 175 11 7179 7184 10.4049/jimmunol.175.11.7179 2-s2.0-28244476478 16301621
129 Hayashida Y. Goi T. Hirono Y. Katayama K. Urano T. Yamaguchi A. PPP1R3 gene (protein phosphatase 1) alterations in colorectal cancer and its relationship to metastasis Oncology Reports 2005 13 6 1223 1227 10.3892/or.13.6.1223 15870946
130 Kim M. Lee E. Zang D. Y. Novel genes exhibiting DNA methylation alterations in Korean patients with chronic lymphocytic leukaemia: a methyl-CpG-binding domain sequencing study Scientific Reports 2020 10 1 p. 1085 10.1038/s41598-020-57919-6
131 Moreno D. A. Scrideli C. A. Cortez M. A. A. Research paper: differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia British Journal of Haematology 2010 150 6 665 673 10.1111/j.1365-2141.2010.08301.x 2-s2.0-77956309330 20636436
132 Shinawi T. Hill V. Dagklis A. KIBRA gene methylation is associated with unfavorable biological prognostic parameters in chronic lymphocytic leukemia Epigenetics 2012 7 3 211 215 10.4161/epi.7.3.19222 2-s2.0-84858220295 22430796
133 Slipicevic A. Jørgensen K. Skrede M. Fatty acid binding protein 7 (FABP7) is involved in the proliferation and invasion of melanoma cells BMC Cancer 2008 8 1 13 10.1186/1471-2407-8-276 2-s2.0-54549086871 18173856
134 Fabbri G. Rasi S. Rossi D. Analysis of the chronic lymphocytic leukemia coding genome: role of NOTCH1 mutational activation Journal of Experimental Medicine 2011 208 7 1389 1401 10.1084/jem.20110921 2-s2.0-79960353160 21670202
135 Dristy T. T. Noor A. R. Dey P. Saha A. Structural analysis and conformational dynamics of SOCS1 gene mutations involved in diffuse large B-cell lymphoma Gene 2023 864 147293 10.1016/j.gene.2023.147293
136 Dumoutier L. Leemans C. Lejeune D. Kotenko S. V. Renauld J. C. Cutting edge: STAT activation by IL-19, IL-20 and mda-7 through IL-20 receptor complexes of two types The Journal of Immunology 2001 167 7 3545 3549 10.4049/jimmunol.167.7.3545 2-s2.0-0035478639 11564763
137 Francois D. T. Katona I. M. June C. H. Wahl L. M. Mond J. J. Examination of the inhibitory and stimulatory effects of IFN-α, β, and γ on human B-cell proliferation induced by various B-cell mitogens Clinical Immunology and Immunopathology 1988 48 3 297 306 10.1016/0090-1229(88)90023-2 2-s2.0-0023732817 3135963
138 Arruga F. Gizdic B. Bologna C. Mutations in NOTCH1 PEST domain orchestrate CCL19-driven homing of chronic lymphocytic leukemia cells by modulating the tumor suppressor gene DUSP22 Leukemia 2017 31 9 1882 1893 10.1038/leu.2016.383 2-s2.0-85011003344 28017968
139 Garding A. Bhattacharya N. Haebe S. TCL1A and ATM are co-expressed in chronic lymphocytic leukemia cells without deletion of 11q Haematologica 2013 98 2 269 273 10.3324/haematol.2012.070623 2-s2.0-84875308387 22875623
140 O’Hayre M. Niederst M. Fecteau J. F. Mechanisms and consequences of the loss of PHLPP1 phosphatase in chronic lymphocytic leukemia (CLL) Leukemia 2012 26 7 1689 1692 10.1038/leu.2012.6 2-s2.0-84863783409 22237780
141 Martinelli S. Maffei R. Fiorcari S. The expression of endothelin-1 in chronic lymphocytic leukemia is controlled by epigenetic mechanisms and extracellular stimuli Leukemia Research 2017 54 17 24 10.1016/j.leukres.2016.12.006 2-s2.0-85009164614 28092772
142 Jang Y. H. Namkoong S. Kim Y. M. Lee S. J. Park B. J. Min D. S. Cleavage of phospholipase D1 by caspase promotes apoptosis via modulation of the p53-dependent cell death pathway Cell Death & Differentiation 2008 15 11 1782 1793 10.1038/cdd.2008.111 2-s2.0-54049158044 18636075
143 Moskalev E. A. Jandaghi P. Fallah M. GHSR DNA hypermethylation is a common epigenetic alteration of high diagnostic value in a broad spectrum of cancers Oncotarget 2015 6 6 4418 4427 10.18632/oncotarget.2759 2-s2.0-84924253305 25557172
144 Latif F. Tory K. Gnarra J. Identification of the von Hippel-Lindau disease tumor suppressor gene Science 1993 260 5112 1317 1320 10.1126/science.8493574 2-s2.0-0027240519 8493574
145 Vargova K. Curik N. Burda P. MYB transcriptionally regulates the miR-155 host gene in chronic lymphocytic leukemia Blood 2011 117 14 3816 3825 10.1182/blood-2010-05-285064 2-s2.0-79953822796 21296997
146 Bos M. K. Deger T. Sleijfer S. Martens J. W. M. Wilting S. M. ESR1 methylation measured in cell-free DNA to evaluate endocrine resistance in metastatic breast cancer patients International Journal of Molecular Sciences 2022 23 10 p. 5631 10.3390/ijms23105631 35628441
147 Roma A. Spagnuolo P. A. Estrogen receptors alpha and beta in acute myeloid leukemia Cancers 2020 12 4 p. 907 10.3390/cancers12040907
148 Navarrete-Meneses M. P. Pérez-Vera P. Epigenetic alterations in acute lymphoblastic leukemia Boletín Médico del Hospital Infantil de México 2017 74 4 243 264 10.1016/j.bmhime.2018.01.004 29382514
149 Maass N. Hojo T. Zhang M. Sager R. Jonat W. Nagasaki K. Maspin-A novel protease inhibitor with tumor-suppressing activity in breast cancer Acta Oncologica 2000 39 8 931 934 10.1080/02841860050215909 2-s2.0-0034500705 11206999
150 Maffei R. Fiorcari S. Bulgarelli J. Endothelium-mediated survival of leukemic cells and angiogenesis-related factors are affected by lenalidomide treatment in chronic lymphocytic leukemia Experimental Hematology 2014 42 2 126 136.e1 10.1016/j.exphem.2013.10.007 2-s2.0-84896727745 24212063
151 Pramil E. Herbi Bastian L. Denèfle T. Targeting chronic lymphocytic leukemia with N-methylated thrombospondin-1–derived peptides overcomes drug resistance Blood Advances 2019 3 20 2920 2933 10.1182/bloodadvances.2019000350 31648314
152 Pu J. Ai T. Weng W. TJP1, a membrane-expressed protein, is a potential therapeutic and prognostic target for lung cancer Technology in Cancer Research and Treatment 2022 21 10.1177/15330338221106855
153 Hanoun M. Eisele L. Suzuki M. Epigenetic silencing of the circadian clock gene CRY1 is associated with an indolent clinical course in chronic lymphocytic leukemia PLoS One 2012 7 3 e34347 10.1371/journal.pone.0034347 2-s2.0-84859015067
154 Dunwell T. L. Dickinson R. E. Stankovic T. Frequent epigenetic inactivation of the SLIT2 gene in chronic and acute lymphocytic leukemia Epigenetics 2009 4 265 269 10.4161/epi.9137 2-s2.0-69949088319 19550140
155 Appe A. J. Aggerholm A. Hansen M. C. Differential expression levels and methylation status of ROBO1 in mantle cell lymphoma and chronic lymphocytic leukaemia The International Journal of Literary Humanities 2017 39 3 70 73 10.1111/ijlh.12615 2-s2.0-85007047362
156 Chen S. S. Johnson A. J. Claus R. Sablitzky F. Plass C. Byrd J. C. L. Loss of Id4 accelerates CLL progression in TCL1 mice Blood 2008 112 11 p. 3153 10.1182/blood.V112.11.3153.3153
157 Weiler S. Ademokun J. A. Norton J. D. ID helix-loop-helix proteins as determinants of cell survival in B-cell chronic lymphocytic leukemia cells in vitro Molecular Cancer 2015 14 1 p. 30 10.1186/s12943-014-0286-9 2-s2.0-84928663914
158 Chen S. S. Claus R. Lucas D. M. Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL Blood 2011 117 3 862 871 10.1182/blood-2010-05-284638 2-s2.0-78751682784 21098398
159 Slupsky J. R. Does B cell receptor signaling in chronic lymphocytic leukaemia cells differ from that in other B cell types? Scientific 2014 2014 14 208928 10.1155/2014/208928
160 Motiwala T. Majumder S. Kutay H. Methylation and silencing of protein tyrosine phosphatase receptor type O in chronic lymphocytic leukemia Clinical Cancer Research 2007 13 11 3174 3181 10.1158/1078-0432.ccr-06-1720 2-s2.0-34250658446 17545520
161 Wakim J. Arman E. Becker-Herman S. The PTPROt tyrosine phosphatase functions as an obligate haploinsufficient tumor suppressor in vivo in B-cell chronic lymphocytic leukemia Oncogene 2017 36 26 3686 3694 10.1038/onc.2016.523 2-s2.0-85011632743 28166196
162 Yamada H. Y. Gorbsky G. J. Tumor suppressor candidate TSSC5 is regulated by UbcH6 and a novel ubiquitin ligase RING105 Oncogene 2006 25 9 1330 1339 10.1038/sj.onc.1209167 2-s2.0-33644761736 16314844
163 Kaderi M. A. Kanduri M. Buhl A. M. LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia Haematologica 2011 96 8 1153 1160 10.3324/haematol.2010.039396 2-s2.0-79961085844 21508119
164 Daugaard I. Hussmann D. Kristensen L. Chronic lymphocytic leukemia patients with heterogeneously or fully methylated LPL promotor display longer time to treatment Epigenomics 2018 10 9 1155 1166 10.2217/epi-2018-0020 2-s2.0-85053871407 30182737
165 Latini F. R. M. Hemerly J. P. Freitas B. C. G. Oler G. Riggins G. J. Cerutti J. M. ABI3 ectopic expression reduces in vitro and in vivocell growth properties while inducing senescence BMC Cancer 2011 11 1 p. 11 10.1186/1471-2407-11-11 2-s2.0-78651073256
166 Sjödin A. Guo D. Sørhaug S. Bjermer L. Henriksson R. Hedman H. Dysregulated secretoglobin expression in human lung cancers Lung Cancer 2003 41 1 49 56 10.1016/S0169-5002(03)00126-0 2-s2.0-0038121537 12826312
167 Tsagiopoulou M. Papakonstantinou N. Moysiadis T. DNA methylation profiles in chronic lymphocytic leukemia patients treated with chemoimmunotherapy Clinical Epigenetics 2019 11 1 p. 177 10.1186/s13148-019-0783-1 31791414
168 Tzorakoleftheraki S.-E. Iliadis A. Kostopoulos I. Koletsa T. TdT expression in normal and neoplastic sebaceous cells Histopathology 2017 71 6 985 988 10.1111/his.13304 2-s2.0-85030089328 28677299
169 McGraw T. P. Folds J. D. Bollum F. J. Stass S. A. Terminal deoxynucleotidyl transferase-positive acute myeloblastic leukemia American Journal of Hematology 1981 10 3 251 258 10.1002/ajh.2830100304 2-s2.0-0019434646 6264782
170 Loi E. Moi L. Fadda A. Methylation alteration of SHANK1 as a predictive, diagnostic and prognostic biomarker for chronic lymphocytic leukemia Oncotarget 2019 10 48 4987 5002 10.18632/oncotarget.27080 31452839
171 Apel E. D. Lewis R. M. Grady R. M. Sanes J. R. Syne-1, A dystrophin- and klarsicht-related protein associated with synaptic nuclei at the neuromuscular junction Journal of Biological Chemistry 2000 275 41 31986 31995 10.1074/jbc.M004775200 2-s2.0-0034644646 10878022
172 Jiang D. Wu X. Sun X. Bone mesenchymal stem cell-derived exosomal microRNA-7-5p inhibits progression of acute myeloid leukemia by targeting OSBPL11 Journal of Nanobiotechnology 2022 20 1 p. 29 10.1186/s12951-021-01206-7
173 Murakami Y. Involvement of a cell adhesion molecule, TSLC1/IGSF4, in human oncogenesis Cancer Science 2005 96 9 543 552 10.1111/j.1349-7006.2005.00089.x 2-s2.0-27144524031 16128739
174 Nakahata S. Saito Y. Marutsuka K. Clinical significance of CADM1/TSLC1/IgSF4 expression in adult T-cell leukemia/lymphoma Leukemia 2012 26 6 1238 1246 10.1038/leu.2011.379 2-s2.0-84862001084 22289924
175 Ando K. Ohira M. Ozaki T. Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation International Journal of Cancer 2008 123 9 2087 2094 10.1002/ijc.23776 2-s2.0-51649085884 18726896
176 Yu Y. P. Yu G. Tseng G. Glutathione peroxidase 3, deleted or methylated in prostate cancer, suppresses prostate cancer growth and metastasis Cancer Research 2007 67 17 8043 8050 10.1158/0008-5472.CAN-07-0648 2-s2.0-34548572037 17804715
177 Takahashi K. Matsumoto C. Ra C. FHL3 negatively regulates human high-affinity IgE receptor β-chain gene expression by acting as a transcriptional co-repressor of MZF-1 Biochemical Journal 2005 386 1 191 200 10.1042/BJ20040775 2-s2.0-14244266613 15453830
178 Yang Y. Hou H. Haller E. M. Nicosia S. V. Bai W. Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation The EMBO Journal 2005 24 5 1021 1032 10.1038/sj.emboj.7600570 2-s2.0-16344384026 15692560
179 Hammarsund M. Corcoran M. M. Wilson W. Characterization of a novel B-CLL candidate gene DLEU7, located in the 13q14 tumor suppressor locus FEBS Letters 2004 556 1-3 75 80 10.1016/S0014-5793(03)01371-1 2-s2.0-0347355522 14706829
180 Jia Z. Gao S. M’Rabet N. De Geyter C. Zhang H. Sp1 is necessary for gene activation of Adamts17 by estrogen Journal of Cellular Biochemistry 2014 115 10 1829 1839 10.1002/jcb.24855 2-s2.0-84906079107 24906090
181 Gutman G. A. Chandy K. G. Grissmer S. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels Pharmacological Reviews 2005 57 4 473 508 10.1124/pr.57.4.10 2-s2.0-29844437655 16382104
182 Loeber G. Maurer-Fogy I. Schwendenwein R. Purification, cDNA cloning, and heterologous expression of the human mitochondrial NADP(+)-dependent malic enzyme Biochemical Journal 1994 304 3 687 692 10.1042/bj3040687 7818469
183 Ni J. Hong J. Li Q. Zeng Q. Xia R. Long non-coding RNA CRNDE suppressing cell proliferation is regulated by DNA methylation in chronic lymphocytic leukemia Leukemia Research 2021 105 106564 10.1016/j.leukres.2021.106564
184 Chan A. S. Thorner P. S. Squire J. A. Zielenska M. Identification of a novel gene NCRMS on chromosome 12q21 with differential expression between rhabdomyosarcoma subtypes Oncogene 2002 21 19 3029 3037 10.1038/sj.onc.1205460 2-s2.0-85047696885 12082533
185 Wang L. Q. Wong K. Y. Li Z. H. Chim C. S. Sang Chim C: epigenetic silencing of tumor suppressor long non-coding RNA BM742401 in chronic lymphocytic leukemia Oncotarget 2016 7 50 82400 82410 10.18632/oncotarget.12252 2-s2.0-85004097327 27689399
186 Buhl A. M. Jurlander J. Geisler C. H. CLLU1 expression levels predict time to initiation of therapy and overall survival in chronic lymphocytic leukemia European Journal of Haematology 2006 76 6 455 464 10.1111/j.0902-4441.2005.t01-1-EJH2530.x 2-s2.0-33645513159 16529606
187 Subhash S. Andersson P. O. Kosalai S. T. Kanduri C. Kanduri M. Global DNA methylation profiling reveals new insights into epigenetically deregulated protein coding and long noncoding RNAs in CLL Clinical Epigenetics 2016 8 1 p. 106 10.1186/s13148-016-0274-6 2-s2.0-84991063612
