
==== Front
Cell Death Discov
Cell Death Discov
Cell Death Discovery
2058-7716
Nature Publishing Group UK London

2160
10.1038/s41420-024-02160-7
Review Article
Enhancers in T Cell development and malignant lesions
http://orcid.org/0000-0001-8501-4249
Zhang Tong zhangtong0616@126.com

12
Zou Lin zoulin@shchildren.com.cn

13
1 grid.16821.3c 0000 0004 0368 8293 Clinical Medicine Research Department, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062 China
2 https://ror.org/0220qvk04 grid.16821.3c 0000 0004 0368 8293 Postgraduate School in Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China
3 grid.16821.3c 0000 0004 0368 8293 Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200062 China
17 9 2024
17 9 2024
2024
10 40610 6 2024
20 8 2024
22 8 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Enhancers constitute a vital category of cis-regulatory elements with a Mediator complex within DNA sequences, orchestrating gene expression by activating promoters. In the development of T cells, some enhancers regulate the critical genes, which might also regulate T cell malignant lesions. This review is to comprehensively elucidate the contributions of enhancers in both normal T cell development and its malignant pathogenesis, proposing the idea that the precise subunits of the Mediator complex are the potential drug target for disrupting the specific gene enhancer for T cell malignant diseases.

Subject terms

Acute lymphocytic leukaemia
Lymphoma
https://doi.org/10.13039/501100001809 National Natural Science Foundation of China (National Science Foundation of China) 82270160 82070167 Zou Lin https://doi.org/10.13039/501100002855 Ministry of Science and Technology of the People's Republic of China (Chinese Ministry of Science and Technology) 2023YFC2706401 Zou Lin issue-copyright-statement© Cell Death Differentiation Association (ADMC) 2024
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pmcFacts

The focus points about enhancer roles in human T cell development and differentiation were concentrated on TCR, CDs, and TFs.

The concept of super-enhancer distinguished the characteristics of different enhancers and provided us with a new perspective on enhancer-driven pathogenic genes.

Disruption of the enhancers, including gene mutation became one of the most important causes of T cell malignancies.

The existing enhancer function inhibitors including BET or CDK inhibitors have achieved certain therapeutic effects in clinical trials, but at the same time, also brought numerous side effects because of they generally lacking specificity.

The human Mediator complex is expected to serve as a specific target for blocking the related enhancer-promoter looping structure, especially the MED1 and MED12 subunits, which can bind to specific eRNAs.

Open questions

Can we find a better way to dynamically monitor the role of enhancers in the T cell differentiation process?

Is it necessary to establish one enhancer database, whose contents include the unified standard enhancer ID, the enhancer sequences, the enhancer-driven genes, super-enhancer identification, etc.?

Do the human T cell lymphotropic virus have their preferences when they infect human T cells and select insertion DNA sequence sites?

How to develop targeted drugs that can bind specifically to different eRNAs and disrupt related enhancer–promoter looping structures?

Introduction

T lymphocytes originate from early lymphoid progenitors (ELPs), which develop lymphoid-primed multipotent progenitors [LMPPs]/common lymphoid progenitors [CLPs]), migrate from the bone marrow (in adults) or liver (during fetal life) to the thymus, where they undergo a series of developmental processes including differentiation, selection, maturation, and eventual export to peripheral tissues. The thymus provides a specialized microenvironment conducive to T lymphocyte development and continuously receives input from ELPs, which acquire a definitive T cell identity to generate mature αβTCR and γδTCR T cells. Early T cell precursors (ETPs), the first phenotypically distinct T cell progenitors derived from LMPPs/CLPs, exhibit a specific cell surface marker phenotype (CD3−/CD4−/CD8low/CD25−/CD44hi/KIT+) [1]. Under the influence of cytokines and transcription factors, ETPs undergo expansion and differentiation into CD4−CD8− double-negative (DN) T cells, which subsequently express TCR. DN T cells undergo TCR rearrangement to generate CD4+CD8+ double-positive (DP) T cells. DP T cells undergo negative selection at the corticomedullary junction of the thymus, giving rise to CD4+ or CD8+ single-positive (SP) T cells that ultimately enter the periphery as naive T cells exhibiting CD45RA+CCR7+ phenotypes [2, 3]. In these stages of T cell development, the regulation of critical genes contributes to its normal function.

Throughout the normal functions of T cell development related to the genomic DNA, including gene enhancer sequences, undergoes accurately orchestrated regulation by a complex network of signaling pathways, ensuring the proper execution of each developmental stage. Effective T cell development, maturation, and functions in vivo hinge upon the accurate progression of each phase, which enhances their important role. Deviations from the correct developmental trajectory, often accompanied by genetic mutations, can result in cell cycle arrest and the onset of malignant diseases. Each stage of T cell development manifests distinct characteristics and relies on the precise orchestration of specific regulatory factors. This review mainly summarizes the pivotal roles of enhancers within the intricate regulatory landscape of T cells, the T cell malignancies, as well as the related clinical trials based on enhancers for T cell leukemia/lymphoma. Notably, we provide the idea that targeted intervention for specific gene enhancers may be a potential therapeutic approach for T cell malignancies.

Characteristics and identification of enhancers

Since the establishment of DNA as the genetic material and the discovery of its double-helix structure in the last century, persistent efforts have been directed towards unraveling the functions of each DNA fragment [4]. Increasingly, the traditional non-coding regions of DNA are recognized to play crucial roles in the development and differentiation of cells. The concept of enhancers was initially proposed in 1981 when a 72 bp repeated DNA segment was identified to be capable of enhancing SV40 globin gene expression [5]. Although enhancers exhibit a close functional relationship with promoters, they diverge significantly from them. Enhancers are typically considered to target promoters and augment their abilities but not target genes directly. Consequently, enhancers increase the expression of target genes through enhancer-promoter communication. Various components engage in the active enhancer–promoter looping structure, including Mediator complex, bromodomain-containing protein (BRD), cyclin-dependent kinases (CDKs), RNA polymeraseII (RNA-PolII), transcription factors (TFs), and methylated promoter [6].

The enhancer, as an inherent element of DNA, drives naturally the related-gene expression. Certainly, the enhancer functions are influenced by chromatin accessibility, histone modification, DNA mutation, TFs recruitment, and cytokines exposure. These interfering conditions have a more significant impact on super-enhancer functions. Briefly, the higher levels of chromatin accessibility, H3 lysine 27 acetylation (H3K27ac), and histone H3 lysine 4 monomethylation (H3K4me1), together with the lower level of trimethylation of histone H3 lysine 4 (H3K4me3) are indeed a representative hallmark that enhancers are more active. TFs recruitment is a necessary step before enhancer plating its roles. DNA mutation, including chromatin structural variations (SVs), could revolutionize the enhancer functions, over activation or complete silence. Some cytokines, such as prolactin and interleukin-2, strengthen the functions of some specific enhancers [7].

In recent decades, novel methodologies have been established to assess potential sequence sites of enhancers. Particularly, H3K27ac is a prominent hallmark of gene enhancers. Abundant new enhancers using H3K27ac reporter assays have been identified [8]. Additionally, H3K4me1, another evolutionarily conserved feature of enhancer chromatin, is enriched at active and primed enhancers while being depleted in H3K4me3 [9, 10].

However, recent insights gained through CRISPR/Cas9 methods coupled with single-cell RNA sequencing unveil that only approximately 10% of enhancers identified by H3K27ac characteristics demonstrate actual enhancer activities. Furthermore, the development of massively parallel reporter assays (MPRA) seeks to elucidate the precise spatial and temporal activity of enhancers, promising extensive application across diverse specimens [11]. Regarding H3K4me1, it remains ambiguous whether it governs or merely correlates with enhancer activity and function [12].

Therefore, recent studies aim to identify genome enhancers that typically incorporate two or more enhancer characteristics. For instance, researchers may consider both high levels of H3K27ac and H3K4me1, or high levels of H3K27ac and H3K4me1 combined with low levels of H3K4me3. In an effort to better discriminate enhancers with varying activities and their capacity to regulate gene expression levels, Professor Young first introduced the concept of super-enhancers in 2013 as a departure from conventional enhancers, which must meet four criteria: longer sequence size, higher transcription factor density and content, stronger activate transcription ability, and greater sensitivity to perturbation, thus distinguishing them from typical enhancers [13, 14].

However, the quantitative standards to evaluate whether an enhancer qualifies as a super-enhancer are still lacking. In subsequent reports on super-enhancers, researchers divided super-enhancers according to their own understanding criterion. Nevertheless, the concept of super-enhancers carries significant implications for the field of enhancer research.

The roles of enhancers in normal t cell differentiation and development

The differentiation and development of normal T cells encompass several crucial stages, commencing with the migration of hematopoietic stem cells (HSCs) into the thymus. These HSCs undergo progressive differentiation into ETP, CD4−CD8− DN T cells, CD4+CD8+ DP T cells, and ultimately CD4+CD8−/CD4−CD8+ SP T cells, following a predetermined sequence [2].

Accumulating studies have provided valuable insights into the roles of enhancers in normal T-cell differentiation and development. Particularly, the investigation into enhancers’ regulation of T cell differentiation and development garnered significant interest during two distinct periods: around 2000 and after 2015. The latter flow in interest can be attributed to the revolutionary advancements in detection technologies and experimental methods related to enhancers. For instance, in 2007, H3K4me1 was first utilized to predict enhancer chromatin, followed by the recognition of H3K27ac as a widely accepted identification standard for active enhancers in 2010 [15]. Furthermore, the advent of CRISPR/Cas9 technology facilitated the analysis of human genome enhancers, starting in 2016 [16].

In this part, we summarize the related enhancers and their functions across several critical stages of T cell differentiation and development (Table 1).Table 1 Overview of enhancer roles in normal T cell development.

T cell stages	Enhancers	Relevant genes	Functions	Research model	Reference	
ETP	EBAB, GATA2/NOTCH1 enhancer	Bim, GATA2, NOTCH1	TCR activation and differentiation	Targeting gene knockdown mice	[17–19]	
DN	Eα, Eδ, Eβ, E8I-V, pTα/Pu.1/HES1/HES5/CD4/ETS1 enhancer	pTα, E47, Pu.1(Sfpi1), Pip-1, RUNX1, NOTCH1, BEAD1, CD4, E2A, HEB, NOTCH3, HES1, HES5, CD8, HOXA5-9, ETS1, RUNX3,	TCR differentiation, CD4/CD8 activation, NOTCH signal pathway, HOXA5-9 transcription	Targeting gene knockdown mice, T cell lines	[22–27, 29, 30, 34–39, 75]	
DP	Eα, Eδ, Eβ, E8I-V, CD4/FOXP3/ZAP70 enhancer	CD4, FOXP3, CD8, ZAP70, Mi2b, HEB, E2A, p300	CD4/CD8 activation, TCR differentiation and rearrangement	Children’s thymic tissue, targeting gene knockdown mice, T cell lines	[21, 24, 31, 33, 42–47, 75]	
SP	Eα, Eδ, E8I-V, E4p, E4m, CD4/FOXP3 enhancer	CD4, FOXP3, CD8, LEF1, TCF1, ZEB, TET1, TET3	CD4/CD8 selected expression, T cell phenotype differentiation	Targeting gene knockdown mice, T cell lines	[20, 28, 32, 40, 41, 76]	
EBAB enhancer of Bub1-Acoxl-Bim, GATA2 guanine–adenine–thymine–adenine binding protein 2, Eα TCR alpha enhancer, Eδ TCR δ enhancer, Eβ TCR β enhancer, pTα pre-TCR alpha, E47 basic helix–loop–helix transcription factor E47, Pu.1 Ets family transcription factor Pu.1, Pip1 Pu.1-interacting protein, Sfpi1 spleen focus forming virus proviral integration 1, CSL CBF1/RBP-Jkappa/Suppressor of Hairless/LAG-1, BEAD1 blocking element alpha/delta 1, E2A basic helix–loop–helix transcription factor E2A, HEB HeLa E-box binding protein, HES1/5 Split homolog 1/5, E8I-V CD8 enhancer I–V, LEF1 lymphoid enhancer-binding factor 1, TCF1 T cell factor 1, FOXP3 forkhead box P3, ZAP70 zeta-chain associated protein kinase 70, Mi2b chromatin remodeling factors Mi2b, p300 histone acetyl transferase p300, ZEB zinc-finger E-box-binding transcriptional repressor, E4p CD4 proximal enhancer, E4m CD4 “maturity” enhancer, TET1/3 ten–eleven translocation family 1/3.

Etp

Research on the roles of enhancers in ETP is relatively limited. Bim is reported to be genetically required as a downstream target of TCR signaling for establishing central T cell tolerance and depleting activated T cells in the periphery. The T cell-specific genomic enhancer EBAB regulates the Bcl-2 Interacting Mediator of cell death (Bim) gene expression in ETP, thereby contributing to the promotion of thymic negative selection and the suppression of autoimmunity [17]. Additionally, the absence of the GATA binding protein 2 (GATA2) enhancer and/or notch receptor 1 (NOTCH1) enhancer leads to a reduction in the number of ETP, accompanied by accelerated T cell apoptosis and aberrant differentiation [18, 19].

DN and DP T Cells

DN and DP stages represent critical phases of normal T cell differentiation and development throughout the entire T cell lifecycle. The question of how enhancers influence the transition from DN to DP stage T cells has been a focal point since the introduction of the concept of enhancers. Early research predominantly concentrated on identifying enhancers related to T lymphocytes [20, 21]. Enhancers play vital roles in TCR expression and rearrangement, encompassing almost every part of the TCR, including TCR α, β, γ, and δ [22–28]. Not only do enhancers of the TCR contribute to this process, but enhancers of related genes also regulate normal differentiation and development processes from DN to DP stages. For instance, enhancers of HES1/5 have been implicated in this transition [29]. Additionally, CD4 and CD8, characteristic positive markers of T lymphocytes, are regulated by enhancers controlling their expression from DN to DP stages [30].

TFs, for example, LEF1 [31, 32], TCF1 [33], E47 [34], NOTCH1 [23], RUNX1 [35], and E2A-HEB [25], bind to TCR enhancers, initiating TCR expression. Conversely, BEAD1 serves as an enhancer-blocking element, preventing the TCR δ enhancer from activating TCR δ gene segment transcription and rearrangement [36, 37]. The PU.1 enhancer exhibits myeloid-specific activity, activating the PU.1 gene in myeloid cells while remaining silent in lymphocytes [38]. ETS1 enhancer activity is attained at the DP stage, facilitating the transition of DN to DP thymocytes [39]. However, E47, in combination with PU.1, exerts a synergistic effect on the activity of the pTα enhancer in DN stage T cells [34].

SP T cells

The SP stage marks the traditional formation of mature lymphocytes. In CD4+CD8− SP stage T cells (T helper), the CD4 gene is regulated by three distinct enhancers (Eα/β/δ) for its expression [20, 21]. Furthermore, enhancers of related genes exert a significant influence on CD4 gene expression. For instance, E4p, in combination with E4m, promotes CD4 gene expression by facilitating CD4 gene demethylation [40]. On the contrary, zinc finger/homeodomain transcription factor (ZEB) acts to silence the CD4 proximal enhancer [41]. Upon transition from the DP stage to the CD4+CD8− SP stage, innumerable factors, including ZAP70 [42], Mi2b, HEB, E2A, and p300 [43], become inactive.

In addition, demethylated forkhead box protein 3 (FOXP3) is associated with a stable Treg phenotype [44]. In CD4−CD8+ SP stage T cells (T cytotoxic) [26, 45–47], there are six diverse CD8 enhancers (E8I-VI) regulating CD8 gene expression. All E8I-VI enhancers are required for CD8 expression in DP and CD4−CD8+ SP stage T cells.

The regulated functions of enhancers in t cell malignancies

The profound effects of enhancers on the occurrence and progression of T cell malignancies manifest in two main aspects: T cell genomic enhancement abnormally changing (Table 2), and leukemia virus enhancers inserting T cell DNA sequences (Table 3). It is worth noting that certain fragments of leukemia virus DNA can interfere with T-cell gene enhancers. These mutations disrupt the normal expression of wild-type T-cell DNA, consequently heightening leukemogenicity.Table 2 Overview of enhancer roles on T cell leukemia/lymphoma.

Disease	Enhancer	Related genes	Mutant site	Functions	Research model	Reference	
T-ALL	Eα, Eδ, Eβ, GIMAP/MYC/TP73 enhancer	GIMAP, TAL1, NOTCH1, TCF1, MYC, IL2RA(CD25), CD30, FYN, TIAM2, TP73	TAL1, E-proteins, MYC, TP73 exons 2–3	TCR translocation, impairing T-ALL development, T cell activation pathway,	Patients’ primary leukemia cells, targeting gene transgenic zebrafish, T-ALL cell lines	[49, 50, 54–56]	
Lymphoma	Eβ, BCL11b/TOX2 enhancer	PDCD1, CXCR5, BCL6, BCL11b, BATF3, IL2R, TOX2	Eβ	aberrant V(D)J cleavages, blocking T cell development and developing lymphoid malignancies	Primary human Tfh and Teff cells, targeting gene transgenic mice, lymphoma cell lines	[48, 77–80]	
T-ALL T cell acute lymphoblastic leukemia, Eα TCR alpha enhancer, Eδ TCR δ enhancer, Eβ TCR β enhancer, GIMAP GTPase of immunity-associated protein, TAL1 T cell acute lymphoblastic leukemia 1, IL2RA interleukin 2 receptor alpha, TIAM2 T cell lymphoma invasion and metastasis 2, Tfh cells T follicular helper cells, Teff T effector cells, BATF3 basic leucine zipper atf-like transcription factor 3, IL2R interleukin 2 receptor.

Table 3 Overview of virus enhancer roles on T cell leukemia/lymphoma.

Disease	Virus	Enhancer	Related genes	Mutant site	Functions	Research model	Reference	
T-ALL	HTLV1, M-MuLV	HTLV1 PuB2/p30II/Tax, HTLV1/MuLVs enhancer	ETS1, ELF1, MYC, EPC1, SRF, ELK1	PuB2, p30II, 10p11.2	Disturbing T cell cycle	Human/mouse T cell lines	[58, 59, 81–84]	
Lymphoma	M-MuLV, SL3-3	MuLV/SL3-3/SV40 enhancer	RUNX1	Runx1	Inducing lymphomas	Mice, human/mouse/rat T cell lines	[60, 85–93]	
M-MuLV moloney murine leukemia virus, EPC1 enhancer of polycomb 1.

Research on virus DNA enhancers was relatively concentrated in the 1990s, as the shorter virus DNA sequences facilitated the elucidation of virus pathogenic mechanisms for T cells. Conversely, in the more complex T cell genome, research on enhancers is still in its initial stage, with the content being more extensive.

Enhancers in T cell leukemia/lymphoma

Disruption of these enhancer elements can hinder T cell differentiation and development, ultimately leading to the onset of T cell leukemia/lymphoma. The TCR serves as a prime example. In normal T cells, the regulatory mechanism of TCR enhancers is relatively well-understood. However, aberrant functions of TCR enhancers can lead to TCR differentiation arrest and rearrangement disorders [48], often accompanied by chromosomal translocations [49].

The NOTCH pathway and its associated proteins regulated by gene enhancers, including MYC and TCF1, are significant pathogenic factors in leukemia. The TCF1-dependent NOTCH1-regulated MYC enhancer plays a fundamental role in shaping the leukemia-prone epigenetic landscape during the transition from preleukemic cells to full-blown disease [50].

Of particular, the enhancer of zeste homolog 2 (EZH2), though EZH2 is not a gene enhancer in humans, it shares a homologous DNA sequence with the enhancer of zeste in drosophilae. EZH2, as an epigenetic regulator, has a critical influence on global H3K27 methylation [51]. Overexpression of EZH2 is commonly observed in T lymphomas and linked to the pSTAT3- MYC pathway [52]. Patients with high EZH2 protein transcripts often exhibit a worse prognosis [53]. Moreover, some studies demonstrate that enhancers can give rise to transcriptional eRNAs (enhancer RNA), which target enhancer-related promoters and exist only briefly. EZH2 provides a compelling example that demonstrates how some enhancers’ sequences can transfer coding-gene functions in the biological evolution process, thereby playing more significant roles.

Furthermore, the driving effects of super-enhancers on oncogenes are garnering more attention, revolutionizing the traditional understanding of abnormal regulatory genes in T cells, to redefine the type, scope, and regulation methods of target genes. Existing evidence suggests that super-enhancers exhibit functional abnormalities in regulating HSC signaling, mitochondrial energy supply, and the expression of anti-tumor proteins in leukemia cells.

Through genomic-level analysis of super-enhancer profiling, researchers have identified multiple previously unreported super-enhancers that are abnormally active in leukemia cells. This discovery provides a new research avenue for further investigating abnormal lesions in leukemia cells. A newly characterized gene, T cell lymphoma invasion and metastasis 2 (TIAM2), is associated with super-enhancers in adult T cell leukemia/lymphoma (ALT) samples, but not in normal T cells [54]. Super-enhancers, including GIMAP, TP73, BCL11b, and MYC enhancers, contribute to inducing leukemia/lymphoma by regulating the expression of TF and cytokines [55, 56].

Importantly, abnormal regulation of gene enhancers can be accompanied by varying degrees of mutations at gene sites, eg. chromatin SVs, which may serve as important targets for drug intervention [57].

Virus enhancers in T cell leukemia/lymphoma

In cases of leukemia/lymphoma induced by viruses such as human T cell lymphotropic virus type 1 (HTLV1), enhancer elements within the viral DNA sequence integrate into the T cell genome, resulting in abnormal expression of certain key proteins in T cells [58]. Currently, it is not fully understood whether leukemia viruses exhibit selectivity for some specific T cell genes that are interfered with by the viruses. Studies on HTLV1, the most common human leukemia virus, and murine leukemia virus (MuLV), commonly used in constructing mouse models in experiments, have shown that genes related to T cell development, in particular, ETS1, ELF1, SRF, and MYC, display functional abnormalities driven by viral enhancers upon T cell infection by the virus [59, 60].

The specific fusion genes driven by the virus enhancer, which plays a decisive role in the onset of leukemia/lymphoma, are still under investigation. A recent theory called enhancer hijacking-mediated oncogenic transcription, based on chromatin SVs, may shed light on the mechanism by which viral enhancers regulate T cell genes, suggesting that TAL1 could hijack the MYCN enhancer, leading to MYCN overexpression [61].

Therapeutic strategies for interrupting abnormal enhancer activities in t cell diseases

The most direct approach to block enhancer-driven gene expression involves gene editing, like knocking out corresponding abnormal enhancer sequences. With the maturation of CRISPR technology, gene editing therapy holds promise as a future treatment method for correcting enhancer abnormalities. However, due to significant differences between in vivo human body environments and cultured cells in vitro, and incomplete understanding of the side effects caused by gene editing, these treatment methods remain confined to cultured cells in vitro or animal experiments.

The enhancer drives the promoter’s function through the enhancer-promoter looping structure. Thus, disrupting or blocking enhancer-promoter looping can effectively inhibit the enhancer’s function. However, the components involved in enhancer-promoter looping are complex, with numerous potential targets for interference.

In the regulatory mechanism of enhancer-promoter looping, the bromodomain and extraterminal (BET) protein family plays a pivotal role in the Mediator complex of RNA-PolII transcription, while CDK regulates the phosphorylation level of RNA-PolII. Consequently, BET or CDK inhibitors, primarily small molecules, represent broad approaches to restrain enhancers’ activities. Additionally, histone acetylation is a prerequisite for activated enhancers’ functions. Therefore, histone acetyltransferase (HAT) inhibitors can disrupt enhancers’ functions [62]. Correspondingly, modulating histone deacetylase (HDAC) expression levels also significantly influences enhancers’ functions.

However, there are limitations to using small molecular inhibitors to suppress enhancers’ activities. BET or CDK inhibitors act as pan-inhibitors, affecting all enhancer activities, such as those necessary for normal gene functions. A part of BET or CDK inhibitors are used as clinical drugs, but most of them lack specificity, which leads to adverse events (AEs) and off-target effects.

Pre-clinical therapeutic strategies

Some BET or CDK inhibitors have been applied to treat T cell malignancies by disrupting abnormal enhancers’ activities. We have compiled published pre-clinical researches on targeting enhancer sites until 2024, summarizing their characteristics and treatment effects (Table 4).Table 4 Summary of pre-clinical therapy based on enhancers in T-ALL.

Drug-name	Drug-target	Therapeutic effects	Research model	Reference	
JQ1	The inhibitor of BET protein	Inducing T-ALL cell apoptosis, inhibiting proliferation	T-ALL cell lines, primary patient T-ALL cells	[94]	
dBET6	The degrader of BET protein	Collapsing the core transcriptional circuitry of T-ALL	T-ALL cell lines, naive CD4+/CD45RA+ T cells, primary PDX samples	[63]	
JQ1	The inhibitor of the BET protein	Reducing T-ALL cell viability, suppressing PDX cell growth	T-ALL cell lines, PDX	[95]	
OTX015	The inhibitor of the BET protein	Suppressing T-ALL cell proliferation and promoting apoptosis, reducing tumor growth	T-ALL cell lines, PDX	[64]	
ARV‑825	The degrader of BET protein	Inhibiting T-ALL cell proliferation, reducing tumor growth	T-ALL cell lines, PDX	[65]	
JQ1, GSK343, OTX015	The inhibitor of BET protein and EZH	Prolong T-ALL PDX mice survival time	T-ALL PDX	[96]	
I-BET151	The pan-BET inhibitor	Arresting cellular growth and proliferation	T-ALL cell lines	[66]	
dinaciclib	The CDK inhibitor	Inhibiting T-ALL cell viability, inducing apoptosis, reducing colony formation capacity, and prolonging mice survival time	T-ALL cell lines, the mouse xenograft model	[67]	
alvocidib	The CDK9 inhibitor	Inhibiting the growth of ATL cells both in vitro and vivo and inducing apoptosis and cell cycle arrest	ATL cell lines, primary ATL patients’ cells, and normal CD4+ lymphocytes	[69]	
PIK-75	The inhibitor of PI3K and CDK	Inhibiting T-ALL cell growth and inducing Apoptosis	T-ALL cell lines, primary patient T-ALL cells	[68]	
PDX patient-derived xenograft.

JQ1 is a typical and commonly used BET inhibitor. It has been applied alone or in combination with other BET inhibitors, for instance, GSK343 and OTX015, to suppress the proliferation of T cell acute lymphoblastic leukemia (T-ALL) cells, and promote their apoptosis. Furthermore, these treatments have shown significant improvements in the survival time of primary patient-derived xenograft (PDX) mice. Novel BET inhibitors continue to be discovered, including dBET6, OTX015, ARV-825, and I-BET151. dBET6 is particularly effective in degrading BET proteins, especially bromodomain-containing protein 4 (BRD4), in T-ALL cells. It disrupts the interaction between enhancers and promoters, leading to specific downregulation of phosphorylated RNA-PolII on Ser2, thereby disrupting the core transcriptional circuitry and global productive transcription elongation [63]. OTX015 specifically inhibits BRD2 [64], while ARV-825 is a highly effective BET protein degrader targeting BRD2, BRD3, and BRD4. ARV-825 exhibits a stronger anti-proliferative effect and lower IC50 than JQ1, dBET1, and OTX015 in T-ALL cell lines [65]. I-BET151, a pan-BET inhibitor, disrupts RUNX1-driven pathogenic super-enhancers by inducing a broad reduction in H3K27ac levels in T-ALL [66].

While fewer studies have focused on CDK inhibitors for T-ALL pre-clinical treatments compared to BET inhibitors, The CDK inhibitor dinaciclib suppresses c-MYC and cyclin T1, induces G2/M phase cell cycle arrest, and triggers apoptosis in T-ALL cells [67]. PIK-75, an inhibitor of PI3K and CDK, has been shown to reduce enhancer activities driven by TAL1 [68]. Additionally, Alvocidib specifically inhibits CDK9, reducing IRF4 expression via super-enhancer suppression [69]. These findings suggest the efficacy of BET and CDK inhibitors in treating T-cell malignancies by suppressing abnormal enhancer activity.

Currently, pre-clinical studies primarily focus on understanding the functions of enhancer inhibitors for T lymphocytes. These studies involve existing cell lines, primary T cells obtained from patients, and PDX mice models. The consensus among researchers is that disrupting aberrant high-active enhancers, some of which may be caused by gene structure variations, is necessary for effective treatment.

A new regulatory mechanism has emerged, highlighting the importance of histone acetylation and deacetylation processes mediated by HATs and HDACs, respectively. Interestingly, despite having opposite catalytic functions, both HAT inhibitors and HDAC inhibitors demonstrate anti-cancer effects [70, 71]. In the context of T-ALL research, more exploration has been conducted on the regulatory roles of HDAC inhibitors on enhancers [72].

Although most enhancer inhibitors have demonstrated superior cytotoxicity by promoting apoptosis and arresting the cell cycle in T leukemia/lymphoma cells, translating these findings into effective clinical therapeutic regimens remains challenging. There is still a long road ahead in terms of refining these inhibitors and developing clinical strategies that leverage their therapeutic potential effectively. Further research is needed to optimize their efficacy, minimize off-target effects, and establish safe and effective dosing regimens before they can be widely adopted in clinical practice. Additionally, the complexity of T leukemia/lymphoma and the heterogeneity among patients may necessitate personalized treatment approaches tailored to individual molecular profiles.

Clinical trials completed or in progress based on enhancers

We list all representative clinical trials on clinicaltrials.gov, which investigate T cell leukemia/lymphoma interventional strategies with BET/CDK inhibitors treatment, based on enhancers (Table 5). Most of them are in study phase 1 and could be observed with antitumor activities. However, a majority of BET/CDK inhibitors in completed status clinical trials have been reported adverse events (AEs), for example, anemia, neutropenic fever, nausea, fatigue, thrombocytopenia, etc [73, 74]. Generally speaking, clinical therapeutic strategies of suppressing enhancer activities based on BET/CDK inhibitors partly achieve the goals, which still have a distance to be adopted as the formal clinical medication.Table 5 Summary of clinical trial on the BET/CDK inhibitors based on enhancer in T cell malignancies.

Disease	Study ID	Drug-name	Synonyms	Drug-Target	Patients-number	Phase	Status	
ALL	NCT03740334	Ribociclib	—	CDK inhibitor	45	I	Active, not recruiting	
NCT01701375	Palbociclib	PD-0332991	CDK4/6 inhibitor	2	I	Terminated	
ALL/lymphomas	NCT03792256	Palbociclib	PD-0332991	CDK4/6 inhibitor	15	I	Active, not recruiting	
CLL	NCT03739554	Fadraciclib	CYC065	CDK2/9 inhibitor	5	I	Completed	
NCT05168904	Fadraciclib	CYC065	CDK2/9 inhibitor	210	I & II	Suspended	
NCT01580228	Dinaciclib	SCH 727965	CDK1/2/5/9 inhibitor	44	III	Completed	
NCT01627054	AT7519M	—	CDK inhibitor	7	II	Completed	
NCT00446342	SNS-032	—	CDK inhibitor	21	I	Completed	
CLL/lymphomas	NCT00871663	Dinaciclib	SCH 727965	CDK1/2/5/9 inhibitor	123	I	Completed	
NCT01515176	Dinaciclib	SCH 727965	CDK1/2/5/9 inhibitor	36	I & II	Completed	
NCT05665530	PRT2527	—	CDK9 inhibitor	104	I	Recruiting	
NCT03547115	Voruciclib	—	CDK9 inhibitor	100	I	Recruiting	
NHL	NCT02543879	FT-1101	CC-95775	BET inhibitor	94	I	Completed	
NCT04089527	FT-1101	CC-95775	BET inhibitor	24	I	Completed	
NCT03220347	BMS-986378	CC-90010	BET inhibitor	139	I	Active, not recruiting	
NCT00871910	Dinaciclib	SCH 727965	CDK1/2/5/9 inhibitor	81	I	Completed	
NCT05758610	Euthare-155008	—	CDK4/6 inhibitor	60	I	Recruiting	
NCT00147485	AG-024322	—	CDK1/2/4 inhibitor	37	I	Terminated	
NCT00141297	Palbociclib	PD-0332991	CDK4/6 inhibitor	74	I	Completed	
Lymphomas	NCT02711137	INCB057643	—	BET inhibitor	137	I & II	Terminated	
NCT02431260	INCB054329	—	BET inhibitor	69	I & II	Terminated	
NCT01943851	Molibresib	GSK525762	BET inhibitor	111	II	Completed	
NCT01949883	Pelabresib	CPI-0610	BET inhibitor	64	I	Completed	
NCT03936465	BMS-986158	—	BET inhibitor	41	I	Active, not recruiting	
NCT03936465	BMS-986378	CC-90010	BET inhibitor	41	I	Active, not recruiting	
NCT05053971	ZEN-3694	—	BET inhibitor	30	I & II	Recruiting	
NCT03925428	Molibresib besylate	GSK525762C	BET inhibitor	0	I	Withdrawn	
NCT04983810	Fadraciclib	CYC065	CDK2/9 inhibitor	330	I & II	Recruiting	
NCT01564251	GDC-0575	—	CDK inhibitor	104	I	Completed	
ID identify, NHL non-Hodgkin lymphoma.

Conclusion and perspectives

The essential roles of enhancers in T cell development are summarized (Fig. 1). Although the comprehension of the functions and roles of enhancers in T cell development and differentiation is limited, we notice that TFs binding enhancers regulate downstream genes, the most involved TCRs, CDs, NOTCH signaling pathway. Therefore, TFs have a pivotal influence on the process of enhancers driving promoters. More researches are needed to reveal the alternation of different enhancer active levels in different stages of T cells, which favors us with a better understanding of T cells tumorigenesis.Fig. 1 Regulation of the key genes in T cell development through enhancer-promoter looping.

The enhancer recruits TFs, such as TAL1, RUNX1, TCF1, BEAD1, and LEF1, and enhancer–promoter looping becomes active. The enhancer drives the related promoter, then gene transcription starts. Current researches reveal that expression of TCRs, selection of CD4 or/and CD8, and NOTCH signal pathway in T cells are closely dependent on enhancers. Abbreviations: TF transcription factor, TCR T cell receptor, HAT histone acetyltransferase, HDAC histone deacetylase.

The concept of super-enhancers brightens us to establish a reasonably and systemically classificatory rules of enhancers. However, there is still no quantitative standard to identify whether an enhancer is typical-enhancer or super-enhancer. H3K27ac and H3K4me1 are generally adopted in evaluating enhancers, which supplies the possibilities of setting up one enhancer database for recording characteristics and functions of enhancers.

Regarding the regulation of enhancer functions, we mainly focus on blocking enhancer activities. Currently, the most common approach is the use of small molecular chemical compounds to interfere with enhancer-promoter looping. BET inhibitors, which interfere with BRD, and CDK inhibitors, which reduce RNA-PolII phosphorylation levels, are widely used in both clinical and pre-clinical research. Depressingly, most BET/CDK interventional strategies lack specificity and easily raise AEs. Prospectively, we believe that the Mediator complex should be paying more attention as another potential drug target. The human Mediator complex comprises 26 subunits, which form a relatively closed spatial structure when the Mediator complex is activated (Fig. 2). Notably, subunits MED1 and MED12 bind to specific eRNAs, which are associated with the activation of nearby promoters. If we can find some drugs that specifically disrupt any subunit of the abnormal genes’ Mediator complex, this will be progress for the diseases with enhancers dysregulation.Fig. 2 The potential mechanism of enhancer-promoter looping in T cells.

The key elements in enhancer-promoter looping include TFs, Mediator complex (including head, middle, and tail, a total of three parts), MKM, BRD4, and RNA-PolII. The acetylation-related key enzymes, HAT and HDAC, are also vital regulated factors. A The stable status of enhancer–promoter looping. Elements are in a dissociated state. Sometimes, histone has a low acetylation level. B The active status of enhancer-promoter looping. Every element has a physical binding in space. Enhancer recruits TFs and produces eRNA. Mediator complex, MKM, and BRD4 form one big structure. Subunit MED1 and MED12 have a connection with eRNA. Finally, the enhancer drives the related promoter. Abbreviations: MKM mediator kinase module, BRD4 bromodomain-containing protein 4, MED1 mediator complex subunit 1, MED12 mediator complex subunit 12, TF transcription factor, HAT histone acetyltransferase, HDAC histone deacetylase.

Furthermore, by precisely understanding the enhancer landscape and its interaction with functional genes, we may identify therapeutic targets that can restore normal gene expression patterns and inhibit tumor progression. This innovative approach could offer novel avenues for personalized medicine and significantly improve outcomes for patients with T-cell malignancies and other related diseases.

Author contributions

Tong Zhang conceptualized and developed the design of the article, interpreted relevant literature, investigated, visualized, and wrote the original paper. Lin Zou was responsible for review & editing, funding acquisition, and validation. All authors have read and approved the final paper.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82270160, 82070167), key projects from Ministry of Science and Technology of the People’s Republic of China (2023YFC2706401).

Competing interests

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Passaro D Quang CT Ghysdael J Microenvironmental cues for T-cell acute lymphoblastic leukemia development Immunol Rev 2016 271 156 72 27088913
Passaro D, Quang CT, Ghysdael J. Microenvironmental cues for T-cell acute lymphoblastic leukemia development. Immunol Rev. 2016;271:156–72.27088913
2. Kumar BV Connors TJ Farber DL Human T cell development, localization, and function throughout life Immunity 2018 48 202 13 29466753
Kumar BV, Connors TJ, Farber DL. Human T cell development, localization, and function throughout life. Immunity. 2018;48:202–13. 10.1016/j.immuni.2018.01.00729466753
3. Overgaard NH Jung JW Steptoe RJ Wells JW CD4+/CD8+ double-positive T cells: more than just a developmental stage? J Leukoc Biol 2015 97 31 38 25360000
Overgaard NH, Jung JW, Steptoe RJ, Wells JW. CD4+/CD8+ double-positive T cells: more than just a developmental stage? J Leukoc Biol. 2015;97:31–38. 10.1189/jlb.1RU0814-38225360000
4. Watson JD Crick FH Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid Nature 1953 171 737 8 13054692
Watson JD, Crick FH. Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid. Nature. 1953;171:737–8. 10.1038/171737a013054692
5. Banerji J Rusconi S Schaffner W Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences Cell 1981 27 299 308 6277502
Banerji J, Rusconi S, Schaffner W. Expression of a beta-globin gene is enhanced by remote SV40 DNA sequences. Cell. 1981;27:299–308. 10.1016/0092-8674(81)90413-x6277502
6. Richter WF Nayak S Iwasa J Taatjes DJ The Mediator complex as a master regulator of transcription by RNA polymerase II Nat Rev Mol Cell Biol 2022 23 732 49 35725906
Richter WF, Nayak S, Iwasa J, Taatjes DJ. The Mediator complex as a master regulator of transcription by RNA polymerase II. Nat Rev Mol Cell Biol. 2022;23:732–49. 10.1038/s41580-022-00498-335725906
7. Zeng X Willi M Shin HY Hennighausen L Wang C Lineage-specific and non-specific cytokine-sensing genes respond differentially to the master regulator STAT5 Cell Rep 2016 17 3333 46 28009300
Zeng X, Willi M, Shin HY, Hennighausen L, Wang C. Lineage-specific and non-specific cytokine-sensing genes respond differentially to the master regulator STAT5. Cell Rep. 2016;17:3333–46. 10.1016/j.celrep.2016.11.07928009300
8. Tie F Banerjee R Stratton CA Prasad-Sinha J Stepanik V Zlobin A CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila polycomb silencing Development 2009 136 3131 41 19700617
Tie F, Banerjee R, Stratton CA, Prasad-Sinha J, Stepanik V, Zlobin A, et al. CBP-mediated acetylation of histone H3 lysine 27 antagonizes Drosophila polycomb silencing. Development. 2009;136:3131–41. 10.1242/dev.03712719700617
9. Rickels R Herz HM Sze CC Cao K Morgan MA Collings CK Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability Nat Genet 2017 49 1647 53 28967912
Rickels R, Herz HM, Sze CC, Cao K, Morgan MA, Collings CK, et al. Histone H3K4 monomethylation catalyzed by Trr and mammalian COMPASS-like proteins at enhancers is dispensable for development and viability. Nat Genet. 2017;49:1647–53. 10.1038/ng.396528967912
10. Local A Huang H Albuquerque CP Singh N Lee AY Wang W Identification of H3K4me1-associated proteins at mammalian enhancers Nat Genet 2018 50 73 82 29255264
Local A, Huang H, Albuquerque CP, Singh N, Lee AY, Wang W, et al. Identification of H3K4me1-associated proteins at mammalian enhancers. Nat Genet. 2018;50:73–82. 10.1038/s41588-017-0015-629255264
11. Inoue F Ahituv N Decoding enhancers using massively parallel reporter assays Genomics 2015 106 159 64 26072433
Inoue F, Ahituv N. Decoding enhancers using massively parallel reporter assays. Genomics. 2015;106:159–64. 10.1016/j.ygeno.2015.06.00526072433
12. Rada-Iglesias A Is H3K4me1 at enhancers correlative or causative? Nat Genet 2018 50 4 5 29273804
Rada-Iglesias A. Is H3K4me1 at enhancers correlative or causative? Nat Genet. 2018;50:4–5. 10.1038/s41588-017-0018-329273804
13. Whyte WA Orlando DA Hnisz D Abraham BJ Lin CY Kagey MH Master transcription factors and mediator establish super-enhancers at key cell identity genes Cell 2013 153 307 19 23582322
Whyte WA, Orlando DA, Hnisz D, Abraham BJ, Lin CY, Kagey MH, et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell. 2013;153:307–19. 10.1016/j.cell.2013.03.03523582322
14. Lovén J Hoke HA Lin CY Lau A Orlando DA Vakoc CR Selective inhibition of tumor oncogenes by disruption of super-enhancers Cell 2013 153 320 34 23582323
Lovén J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153:320–34. 10.1016/j.cell.2013.03.03623582323
15. Creyghton MP Cheng AW Welstead GG Kooistra T Carey BW Steine EJ Histone H3K27ac separates active from poised enhancers and predicts developmental state Proc Natl Acad Sci USA 2010 107 21931 6 21106759
Creyghton MP, Cheng AW, Welstead GG, Kooistra T, Carey BW, Steine EJ, et al. Histone H3K27ac separates active from poised enhancers and predicts developmental state. Proc Natl Acad Sci USA. 2010;107:21931–6. 10.1073/pnas.101607110721106759
16. Korkmaz G Lopes R Ugalde AP Nevedomskaya E Han R Myacheva K Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9 Nat Biotechnol 2016 34 192 8 26751173
Korkmaz G, Lopes R, Ugalde AP, Nevedomskaya E, Han R, Myacheva K, et al. Functional genetic screens for enhancer elements in the human genome using CRISPR-Cas9. Nat Biotechnol. 2016;34:192–8. 10.1038/nbt.345026751173
17. Hojo MA Masuda K Hojo H Nagahata Y Yasuda K Ohara D Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection Nat Commun 2019 10 2603 31197149
Hojo MA, Masuda K, Hojo H, Nagahata Y, Yasuda K, Ohara D, et al. Identification of a genomic enhancer that enforces proper apoptosis induction in thymic negative selection. Nat Commun. 2019;10:2603 10.1038/s41467-019-10525-131197149
18. You X Zhou Y Chang YI Kong G Ranheim EA Johnson KD Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development Blood Adv 2022 6 1095 9 34516632
You X, Zhou Y, Chang YI, Kong G, Ranheim EA, Johnson KD, et al. Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development. Blood Adv. 2022;6:1095–9. 10.1182/bloodadvances.202100431134516632
19. Kashiwagi M Figueroa DS Ay F Morgan BA Georgopoulos K A double-negative thymocyte-specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and β-selection Nat Immunol 2022 23 1628 43 36316479
Kashiwagi M, Figueroa DS, Ay F, Morgan BA, Georgopoulos K. A double-negative thymocyte-specific enhancer augments Notch1 signaling to direct early T cell progenitor expansion, lineage restriction and β-selection. Nat Immunol. 2022;23:1628–43. 10.1038/s41590-022-01322-y36316479
20. Uematsu Y Donda A De Libero G Thymocytes control the CD4 gene differently from mature T lymphocytes Int Immunol 1997 9 179 87 9043959
Uematsu Y, Donda A, De Libero G. Thymocytes control the CD4 gene differently from mature T lymphocytes. Int Immunol. 1997;9:179–87. 10.1093/intimm/9.1.1799043959
21. Adlam M Duncan DD Ng DK Siu G Positive selection induces CD4 promoter and enhancer function Int Immunol 1997 9 877 87 9199971
Adlam M, Duncan DD, Ng DK, Siu G. Positive selection induces CD4 promoter and enhancer function. Int Immunol. 1997;9:877–87. 10.1093/intimm/9.6.8779199971
22. Tripathi RK Mathieu N Spicuglia S Payet D Verthuy C Bouvier G Definition of a T-cell receptor beta gene core enhancer of V(D)J recombination by transgenic mapping Mol Cell Biol 2000 20 42 53 10594007
Tripathi RK, Mathieu N, Spicuglia S, Payet D, Verthuy C, Bouvier G, et al. Definition of a T-cell receptor beta gene core enhancer of V(D)J recombination by transgenic mapping. Mol Cell Biol. 2000;20:42–53. 10.1128/mcb.20.1.42-53.200010594007
23. Reizis B Leder P Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway Genes Dev 2002 16 295 300 11825871
Reizis B, Leder P. Direct induction of T lymphocyte-specific gene expression by the mammalian Notch signaling pathway. Genes Dev. 2002;16:295–300. 10.1101/gad.96070211825871
24. Spicuglia S Payet D Tripathi RK Rameil P Verthuy C Imbert J TCRalpha enhancer activation occurs via a conformational change of a pre-assembled nucleo-protein complex Embo J 2000 19 2034 45 10790370
Spicuglia S, Payet D, Tripathi RK, Rameil P, Verthuy C, Imbert J, et al. TCRalpha enhancer activation occurs via a conformational change of a pre-assembled nucleo-protein complex. Embo J. 2000;19:2034–45. 10.1093/emboj/19.9.203410790370
25. Tremblay M Herblot S Lecuyer E Hoang T Regulation of pT alpha gene expression by a dosage of E2A, HEB, and SCL J Biol Chem 2003 278 12680 7 12566462
Tremblay M, Herblot S, Lecuyer E, Hoang T. Regulation of pT alpha gene expression by a dosage of E2A, HEB, and SCL. J Biol Chem. 2003;278:12680–7. 10.1074/jbc.M20987020012566462
26. Pekowska A Benoukraf T Zacarias-Cabeza J Belhocine M Koch F Holota H H3K4 tri-methylation provides an epigenetic signature of active enhancers Embo J 2011 30 4198 210 21847099
Pekowska A, Benoukraf T, Zacarias-Cabeza J, Belhocine M, Koch F, Holota H, et al. H3K4 tri-methylation provides an epigenetic signature of active enhancers. Embo J. 2011;30:4198–210. 10.1038/emboj.2011.29521847099
27. Cieslak, A, Charbonnier, G, Tesio, M, Mathieu, EL, Belhocine, M, Touzart, A et al. Blueprint of human thymopoiesis reveals molecular mechanisms of stage-specific TCR enhancer activation. J Exp Med. 2020;217. 10.1084/jem.20192360
28. Bassing CH Tillman RE Woodman BB Canty D Monroe RJ Sleckman BP T cell receptor (TCR) alpha/delta locus enhancer identity and position are critical for the assembly of TCR delta and alpha variable region genes Proc Natl Acad Sci USA 2003 100 2598 603 12604775
Bassing CH, Tillman RE, Woodman BB, Canty D, Monroe RJ, Sleckman BP, et al. T cell receptor (TCR) alpha/delta locus enhancer identity and position are critical for the assembly of TCR delta and alpha variable region genes. Proc Natl Acad Sci USA. 2003;100:2598–603. 10.1073/pnas.043794310012604775
29. Felli MP Maroder M Mitsiadis TA Campese AF Bellavia D Vacca A Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development Int Immunol 1999 11 1017 25 10383933
Felli MP, Maroder M, Mitsiadis TA, Campese AF, Bellavia D, Vacca A, et al. Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development. Int Immunol. 1999;11:1017–25. 10.1093/intimm/11.7.101710383933
30. Sellars M Huh JR Day K Issuree PD Galan C Gobeil S Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages Nat Immunol 2015 16 746 54 26030024
Sellars M, Huh JR, Day K, Issuree PD, Galan C, Gobeil S, et al. Regulation of DNA methylation dictates Cd4 expression during the development of helper and cytotoxic T cell lineages. Nat Immunol. 2015;16:746–54. 10.1038/ni.319826030024
31. Travis A Amsterdam A Belanger C Grosschedl R LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected] Genes Dev 1991 5 880 94 1827423
Travis A, Amsterdam A, Belanger C, Grosschedl R. LEF-1, a gene encoding a lymphoid-specific protein with an HMG domain, regulates T-cell receptor alpha enhancer function [corrected]. Genes Dev. 1991;5:880–94. 10.1101/gad.5.5.8801827423
32. Okamura RM Sigvardsson M Galceran J Verbeek S Clevers H Grosschedl R Redundant regulation of T cell differentiation and TCRalpha gene expression by the transcription factors LEF-1 and TCF-1 Immunity 1998 8 11 20 9462507
Okamura RM, Sigvardsson M, Galceran J, Verbeek S, Clevers H, Grosschedl R. Redundant regulation of T cell differentiation and TCRalpha gene expression by the transcription factors LEF-1 and TCF-1. Immunity. 1998;8:11–20. 10.1016/s1074-7613(00)80454-99462507
33. Ohteki T Wilson A Verbeek S MacDonald HR Clevers H Selectively impaired development of intestinal T cell receptor gamma delta+ cells and liver CD4+ NK1+ T cell receptor alpha beta+ cells in T cell factor-1-deficient mice Eur J Immunol 1996 26 351 5 8617303
Ohteki T, Wilson A, Verbeek S, MacDonald HR, Clevers H. Selectively impaired development of intestinal T cell receptor gamma delta+ cells and liver CD4+ NK1+ T cell receptor alpha beta+ cells in T cell factor-1-deficient mice. Eur J Immunol. 1996;26:351–5. 10.1002/eji.18302602138617303
34. Petersson K Ivars F Sigvardsson M The pT alpha promoter and enhancer are direct targets for transactivation by E box-binding proteins Eur J Immunol 2002 32 911 20 11870636
Petersson K, Ivars F, Sigvardsson M. The pT alpha promoter and enhancer are direct targets for transactivation by E box-binding proteins. Eur J Immunol. 2002;32:911–20. 10.1002/1521-4141(200203)32:3<911::Aid-immu911>3.0.Co;2-h11870636
35. Seo W Muroi S Akiyama K Taniuchi I Distinct requirement of Runx complexes for TCRβ enhancer activation at distinct developmental stages Sci Rep 2017 7 41351 28150718
Seo W, Muroi S, Akiyama K, Taniuchi I. Distinct requirement of Runx complexes for TCRβ enhancer activation at distinct developmental stages. Sci Rep. 2017;7:41351 10.1038/srep4135128150718
36. Zhong XP Krangel MS An enhancer-blocking element between alpha and delta gene segments within the human T cell receptor alpha/delta locus Proc Natl Acad Sci USA 1997 94 5219 24 9144218
Zhong XP, Krangel MS. An enhancer-blocking element between alpha and delta gene segments within the human T cell receptor alpha/delta locus. Proc Natl Acad Sci USA. 1997;94:5219–24. 10.1073/pnas.94.10.52199144218
37. Sleckman BP Carabana J Zhong X Krangel MS Assessing a role for enhancer-blocking activity in gene regulation within the murine T-cell receptor alpha/delta locus Immunology 2001 104 11 18 11576215
Sleckman BP, Carabana J, Zhong X, Krangel MS. Assessing a role for enhancer-blocking activity in gene regulation within the murine T-cell receptor alpha/delta locus. Immunology. 2001;104:11–18. 10.1046/j.1365-2567.2001.01304.x11576215
38. Zarnegar MA Chen J Rothenberg EV Cell-type-specific activation and repression of PU.1 by a complex of discrete, functionally specialized cis-regulatory elements Mol Cell Biol 2010 30 4922 39 20696839
Zarnegar MA, Chen J, Rothenberg EV. Cell-type-specific activation and repression of PU.1 by a complex of discrete, functionally specialized cis-regulatory elements. Mol Cell Biol. 2010;30:4922–39. 10.1128/mcb.00354-1020696839
39. Cauchy P Maqbool MA Zacarias-Cabeza J Vanhille L Koch F Fenouil R Dynamic recruitment of Ets1 to both nucleosome-occupied and -depleted enhancer regions mediates a transcriptional program switch during early T-cell differentiation Nucleic Acids Res 2016 44 3567 85 26673693
Cauchy P, Maqbool MA, Zacarias-Cabeza J, Vanhille L, Koch F, Fenouil R, et al. Dynamic recruitment of Ets1 to both nucleosome-occupied and -depleted enhancer regions mediates a transcriptional program switch during early T-cell differentiation. Nucleic Acids Res. 2016;44:3567–85. 10.1093/nar/gkv147526673693
40. Issuree PD Day K Au C Raviram R Zappile P Skok JA Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development Nat Commun 2018 9 3594 30185805
Issuree PD, Day K, Au C, Raviram R, Zappile P, Skok JA, et al. Stage-specific epigenetic regulation of CD4 expression by coordinated enhancer elements during T cell development. Nat Commun. 2018;9:3594 10.1038/s41467-018-05834-w30185805
41. Brabletz T Jung A Hlubek F Löhberg C Meiler J Suchy U Negative regulation of CD4 expression in T cells by the transcriptional repressor ZEB Int Immunol 1999 11 1701 8 10508188
Brabletz T, Jung A, Hlubek F, Löhberg C, Meiler J, Suchy U, et al. Negative regulation of CD4 expression in T cells by the transcriptional repressor ZEB. Int Immunol. 1999;11:1701–8. 10.1093/intimm/11.10.170110508188
42. Liu X Adams A Wildt KF Aronow B Feigenbaum L Bosselut R Restricting Zap70 expression to CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading mechanism controlling the completion of positive selection J Exp Med 2003 197 363 73 12566420
Liu X, Adams A, Wildt KF, Aronow B, Feigenbaum L, Bosselut R. Restricting Zap70 expression to CD4+CD8+ thymocytes reveals a T cell receptor-dependent proofreading mechanism controlling the completion of positive selection. J Exp Med. 2003;197:363–73. 10.1084/jem.2002169812566420
43. Yu M Wan M Zhang J Wu J Khatri R Chi T Nucleoprotein structure of the CD4 locus: implications for the mechanisms underlying CD4 regulation during T cell development Proc Natl Acad Sci USA 2008 105 3873 8 18322012
Yu M, Wan M, Zhang J, Wu J, Khatri R, Chi T. Nucleoprotein structure of the CD4 locus: implications for the mechanisms underlying CD4 regulation during T cell development. Proc Natl Acad Sci USA. 2008;105:3873–8. 10.1073/pnas.080081010518322012
44. Vanhanen R Leskinen K Mattila IP Saavalainen P Arstila TP Epigenetic and transcriptional analysis supports human regulatory T cell commitment at the CD4+CD8+ thymocyte stage Cell Immunol 2020 347 104026 31843201
Vanhanen R, Leskinen K, Mattila IP, Saavalainen P, Arstila TP. Epigenetic and transcriptional analysis supports human regulatory T cell commitment at the CD4+CD8+ thymocyte stage. Cell Immunol. 2020;347:104026 10.1016/j.cellimm.2019.10402631843201
45. Feik N Bilic I Tinhofer J Unger B Littman DR Ellmeier W Functional and molecular analysis of the double-positive stage-specific CD8 enhancer E8III during thymocyte development J Immunol 2005 174 1513 24 15661911
Feik N, Bilic I, Tinhofer J, Unger B, Littman DR, Ellmeier W. Functional and molecular analysis of the double-positive stage-specific CD8 enhancer E8III during thymocyte development. J Immunol. 2005;174:1513–24. 10.4049/jimmunol.174.3.151315661911
46. Wada H Yasmin N Kakugawa K Ohno-Oishi M Nieke S Miyamoto C Requirement for intron structures in activating the Cd8a locus Proc Natl Acad Sci USA 2018 115 3440 5 29531042
Wada H, Yasmin N, Kakugawa K, Ohno-Oishi M, Nieke S, Miyamoto C, et al. Requirement for intron structures in activating the Cd8a locus. Proc Natl Acad Sci USA. 2018;115:3440–5. 10.1073/pnas.171883711529531042
47. Gülich AF Preglej T Hamminger P Alteneder M Tizian C Orola MJ Differential requirement of Cd8 enhancers E8(I) and E8(VI) in cytotoxic lineage T cells and in intestinal intraepithelial lymphocytes Front Immunol 2019 10 409 30915074
Gülich AF, Preglej T, Hamminger P, Alteneder M, Tizian C, Orola MJ, et al. Differential requirement of Cd8 enhancers E8(I) and E8(VI) in cytotoxic lineage T cells and in intestinal intraepithelial lymphocytes. Front Immunol. 2019;10:409 10.3389/fimmu.2019.0040930915074
48. Kang YH Son CY Lee CH Ryu CJ Aberrant V(D)J cleavages in T cell receptor beta enhancer- and p53-deficient lymphoma cells Oncol Rep 2010 23 1463 8 20372865
Kang YH, Son CY, Lee CH, Ryu CJ. Aberrant V(D)J cleavages in T cell receptor beta enhancer- and p53-deficient lymphoma cells. Oncol Rep. 2010;23:1463–8. 10.3892/or_0000078520372865
49. Le Noir S Ben Abdelali R Lelorch M Bergeron J Sungalee S Payet-Bornet D Extensive molecular mapping of TCRα/δ- and TCRβ-involved chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL Blood 2012 120 3298 309 22948044
Le Noir S, Ben Abdelali R, Lelorch M, Bergeron J, Sungalee S, Payet-Bornet D, et al. Extensive molecular mapping of TCRα/δ- and TCRβ-involved chromosomal translocations reveals distinct mechanisms of oncogene activation in T-ALL. Blood. 2012;120:3298–309. 10.1182/blood-2012-04-42548822948044
50. Antoszewski M Fournier N Ruiz Buendía GA Lourenco J Liu Y Sugrue T Tcf1 is essential for initiation of oncogenic Notch1-driven chromatin topology in T-ALL Blood 2022 139 2483 98 35020836
Antoszewski M, Fournier N, Ruiz Buendía GA, Lourenco J, Liu Y, Sugrue T, et al. Tcf1 is essential for initiation of oncogenic Notch1-driven chromatin topology in T-ALL. Blood. 2022;139:2483–98. 10.1182/blood.202101207735020836
51. Sasaki D Imaizumi Y Hasegawa H Osaka A Tsukasaki K Choi YL Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy Haematologica 2011 96 712 9 21228036
Sasaki D, Imaizumi Y, Hasegawa H, Osaka A, Tsukasaki K, Choi YL, et al. Overexpression of enhancer of zeste homolog 2 with trimethylation of lysine 27 on histone H3 in adult T-cell leukemia/lymphoma as a target for epigenetic therapy. Haematologica. 2011;96:712–9. 10.3324/haematol.2010.02860521228036
52. Shi M Shahsafaei A Liu C Yu H Dorfman DM Enhancer of zeste homolog 2 is widely expressed in T-cell neoplasms, is associated with high proliferation rate and correlates with MYC and pSTAT3 expression in a subset of cases Leuk Lymphoma 2015 56 2087 91 25263318
Shi M, Shahsafaei A, Liu C, Yu H, Dorfman DM. Enhancer of zeste homolog 2 is widely expressed in T-cell neoplasms, is associated with high proliferation rate and correlates with MYC and pSTAT3 expression in a subset of cases. Leuk Lymphoma. 2015;56:2087–91. 10.3109/10428194.2014.96878025263318
53. Zhang H Lv H Jia X Hu G Kong L Zhang T Clinical significance of enhancer of zeste homolog 2 and histone deacetylases 1 and 2 expression in peripheral T-cell lymphoma Oncol Lett 2019 18 1415 23 31423206
Zhang H, Lv H, Jia X, Hu G, Kong L, Zhang T, et al. Clinical significance of enhancer of zeste homolog 2 and histone deacetylases 1 and 2 expression in peripheral T-cell lymphoma. Oncol Lett. 2019;18:1415–23. 10.3892/ol.2019.1041031423206
54. Wong RWJ Ngoc PCT Leong WZ Yam AWY Zhang T Asamitsu K Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia Blood 2017 130 2326 38 28978570
Wong RWJ, Ngoc PCT, Leong WZ, Yam AWY, Zhang T, Asamitsu K, et al. Enhancer profiling identifies critical cancer genes and characterizes cell identity in adult T-cell leukemia. Blood. 2017;130:2326–38. 10.1182/blood-2017-06-79218428978570
55. Liau WS Tan SH Ngoc PCT Wang CQ Tergaonkar V Feng H Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia Leukemia 2017 31 1798 807 28028313
Liau WS, Tan SH, Ngoc PCT, Wang CQ, Tergaonkar V, Feng H, et al. Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia. Leukemia. 2017;31:1798–807. 10.1038/leu.2016.39228028313
56. Ong JZL Yokomori R Wong RWJ Tan TK Ueda R Ishida T Requirement for TP73 and genetic alterations originating from its intragenic super-enhancer in adult T-cell leukemia Leukemia 2022 36 2293 305 35908104
Ong JZL, Yokomori R, Wong RWJ, Tan TK, Ueda R, Ishida T, et al. Requirement for TP73 and genetic alterations originating from its intragenic super-enhancer in adult T-cell leukemia. Leukemia. 2022;36:2293–305. 10.1038/s41375-022-01655-535908104
57. Botten GA Zhang Y Dudnyk K Kim YJ Liu X Sanders JT Structural variation cooperates with permissive chromatin to control enhancer hijacking-mediated oncogenic transcription Blood 2023 142 336 51 36947815
Botten GA, Zhang Y, Dudnyk K, Kim YJ, Liu X, Sanders JT, et al. Structural variation cooperates with permissive chromatin to control enhancer hijacking-mediated oncogenic transcription. Blood. 2023;142:336–51. 10.1182/blood.202201755536947815
58. Awasthi S Sharma A Wong K Zhang J Matlock EF Rogers L A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions Mol Cell Biol 2005 25 6178 98 15988028
Awasthi S, Sharma A, Wong K, Zhang J, Matlock EF, Rogers L, et al. A human T-cell lymphotropic virus type 1 enhancer of Myc transforming potential stabilizes Myc-TIP60 transcriptional interactions. Mol Cell Biol. 2005;25:6178–98. 10.1128/mcb.25.14.6178-6198.200515988028
59. Clark NM Smith MJ Hilfinger JM Markovitz DM Activation of the human T-cell leukemia virus type I enhancer is mediated by binding sites for Elf-1 and the pets factor J Virol 1993 67 5522 8 8350410
Clark NM, Smith MJ, Hilfinger JM, Markovitz DM. Activation of the human T-cell leukemia virus type I enhancer is mediated by binding sites for Elf-1 and the pets factor. J Virol. 1993;67:5522–8. 10.1128/jvi.67.9.5522-5528.19938350410
60. Hanecak R Pattengale PK Fan H Addition of substitution of simian virus 40 enhancer sequences into the Moloney murine leukemia virus (M-MuLV) long terminal repeat yields infectious M-MuLV with altered biological properties J Virol 1988 62 2427 36 2836623
Hanecak R, Pattengale PK, Fan H. Addition of substitution of simian virus 40 enhancer sequences into the Moloney murine leukemia virus (M-MuLV) long terminal repeat yields infectious M-MuLV with altered biological properties. J Virol. 1988;62:2427–36. 10.1128/jvi.62.7.2427-2436.19882836623
61. Tan SH Tan TK Yokomori R Liao M Huang XZ Yeoh AEJ TAL1 hijacks MYCN enhancer that induces MYCN expression and dependence on mevalonate pathway in T-cell acute lymphoblastic leukemia Leukemia 2023 37 1969 81 37591943
Tan SH, Tan TK, Yokomori R, Liao M, Huang XZ, Yeoh AEJ, et al. TAL1 hijacks MYCN enhancer that induces MYCN expression and dependence on mevalonate pathway in T-cell acute lymphoblastic leukemia. Leukemia. 2023;37:1969–81. 10.1038/s41375-023-01993-y37591943
62. Chen Q Yang B Liu X Zhang XD Zhang L Liu T Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents Theranostics 2022 12 4935 48 35836809
Chen Q, Yang B, Liu X, Zhang XD, Zhang L, Liu T. Histone acetyltransferases CBP/p300 in tumorigenesis and CBP/p300 inhibitors as promising novel anticancer agents. Theranostics. 2022;12:4935–48. 10.7150/thno.7322335836809
63. Winter GE Mayer A Buckley DL Erb MA Roderick JE Vittori S BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment Mol Cell 2017 67 5 18.e19 28673542
Winter GE, Mayer A, Buckley DL, Erb MA, Roderick JE, Vittori S, et al. BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment. Mol Cell. 2017;67:5–18.e19. 10.1016/j.molcel.2017.06.00428673542
64. Tian XP Cai J Ma SY Fang Y Huang HQ Lin TY BRD2 induces drug resistance through activation of the RasGRP1/Ras/ERK signaling pathway in adult T-cell lymphoblastic lymphoma Cancer Commun 2020 40 245 59
Tian XP, Cai J, Ma SY, Fang Y, Huang HQ, Lin TY, et al. BRD2 induces drug resistance through activation of the RasGRP1/Ras/ERK signaling pathway in adult T-cell lymphoblastic lymphoma. Cancer Commun. 2020;40:245–59. 10.1002/cac2.12039
65. Wu S Jiang Y Hong Y Chu X Zhang Z Tao Y BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting ‘Undruggable’ Myc-pathway genes Cancer Cell Int 2021 21 230 33888130
Wu S, Jiang Y, Hong Y, Chu X, Zhang Z, Tao Y, et al. BRD4 PROTAC degrader ARV-825 inhibits T-cell acute lymphoblastic leukemia by targeting ‘Undruggable’ Myc-pathway genes. Cancer Cell Int. 2021;21:230 10.1186/s12935-021-01908-w33888130
66. Islam R Jenkins CE Cao Q Wong J Bilenky M Carles A RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia iScience 2023 26 106795 37213235
Islam R, Jenkins CE, Cao Q, Wong J, Bilenky M, Carles A, et al. RUNX1 colludes with NOTCH1 to reprogram chromatin in T cell acute lymphoblastic leukemia. iScience. 2023;26:106795 10.1016/j.isci.2023.10679537213235
67. Moharram SA Shah K Khanum F Marhäll A Gazi M Kazi JU Efficacy of the CDK inhibitor dinaciclib in vitro and in vivo in T-cell acute lymphoblastic leukemia Cancer Lett 2017 405 73 78 28756008
Moharram SA, Shah K, Khanum F, Marhäll A, Gazi M, Kazi JU. Efficacy of the CDK inhibitor dinaciclib in vitro and in vivo in T-cell acute lymphoblastic leukemia. Cancer Lett. 2017;405:73–78. 10.1016/j.canlet.2017.07.01928756008
68. Lim FQ Chan AS Yokomori R Huang XZ Theardy MS Yeoh AEJ Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia Haematologica 2023 108 367 81 36073513
Lim FQ, Chan AS, Yokomori R, Huang XZ, Theardy MS, Yeoh AEJ, et al. Targeting dual oncogenic machineries driven by TAL1 and PI3K-AKT pathways in T-cell acute lymphoblastic leukemia. Haematologica. 2023;108:367–81. 10.3324/haematol.2022.28076136073513
69. Sakamoto H Ando K Imaizumi Y Mishima H Kinoshita A Kobayashi Y Alvocidib inhibits IRF4 expression via super-enhancer suppression and adult T-cell leukemia/lymphoma cell growth Cancer Sci 2022 113 4092 103 36047964
Sakamoto H, Ando K, Imaizumi Y, Mishima H, Kinoshita A, Kobayashi Y, et al. Alvocidib inhibits IRF4 expression via super-enhancer suppression and adult T-cell leukemia/lymphoma cell growth. Cancer Sci. 2022;113:4092–103. 10.1111/cas.1555036047964
70. Baell JB Leaver DJ Hermans SJ Kelly GL Brennan MS Downer NL Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth Nature 2018 560 253 7 30069049
Baell JB, Leaver DJ, Hermans SJ, Kelly GL, Brennan MS, Downer NL, et al. Inhibitors of histone acetyltransferases KAT6A/B induce senescence and arrest tumour growth. Nature. 2018;560:253–7. 10.1038/s41586-018-0387-530069049
71. Romanski A Bacic B Bug G Pfeifer H Gul H Remiszewski S Use of a novel histone deacetylase inhibitor to induce apoptosis in cell lines of acute lymphoblastic leukemia Haematologica 2004 89 419 26 15075075
Romanski A, Bacic B, Bug G, Pfeifer H, Gul H, Remiszewski S, et al. Use of a novel histone deacetylase inhibitor to induce apoptosis in cell lines of acute lymphoblastic leukemia. Haematologica. 2004;89:419–26.15075075
72. Sanchez GJ Richmond PA Bunker EN Karman SS Azofeifa J Garnett AT Genome-wide dose-dependent inhibition of histone deacetylases studies reveal their roles in enhancer remodeling and suppression of oncogenic super-enhancers Nucleic Acids Res 2018 46 1756 76 29240919
Sanchez GJ, Richmond PA, Bunker EN, Karman SS, Azofeifa J, Garnett AT, et al. Genome-wide dose-dependent inhibition of histone deacetylases studies reveal their roles in enhancer remodeling and suppression of oncogenic super-enhancers. Nucleic Acids Res. 2018;46:1756–76. 10.1093/nar/gkx122529240919
73. Dawson MA Borthakur G Huntly BJP Karadimitris A Alegre A Chaidos A A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies Clin Cancer Res 2023 29 711 22 36350312
Dawson MA, Borthakur G, Huntly BJP, Karadimitris A, Alegre A, Chaidos A, et al. A phase I/II open-label study of molibresib for the treatment of relapsed/refractory hematologic malignancies. Clin Cancer Res. 2023;29:711–22. 10.1158/1078-0432.Ccr-22-128436350312
74. Nemunaitis JJ Small KA Kirschmeier P Zhang D Zhu Y Jou YM A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies J Transl Med 2013 11 259 24131779
Nemunaitis JJ, Small KA, Kirschmeier P, Zhang D, Zhu Y, Jou YM, et al. A first-in-human, phase 1, dose-escalation study of dinaciclib, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies. J Transl Med. 2013;11:259 10.1186/1479-5876-11-25924131779
75. Doty RT Xia D Nguyen SP Hathaway TR Willerford DM Promoter element for transcription of unrearranged T-cell receptor beta-chain gene in pro-T cells Blood 1999 93 3017 25 10216098
Doty RT, Xia D, Nguyen SP, Hathaway TR, Willerford DM. Promoter element for transcription of unrearranged T-cell receptor beta-chain gene in pro-T cells. Blood. 1999;93:3017–25.10216098
76. He B Xing S Chen C Gao P Teng L Shan Q CD8(+) T cells utilize highly dynamic enhancer repertoires and regulatory circuitry in response to infections Immunity 2016 45 1341 54 27986453
He B, Xing S, Chen C, Gao P, Teng L, Shan Q, et al. CD8(+) T cells utilize highly dynamic enhancer repertoires and regulatory circuitry in response to infections. Immunity. 2016;45:1341–54. 10.1016/j.immuni.2016.11.00927986453
77. Weinstein JS Lezon-Geyda K Maksimova Y Craft S Zhang Y Su M Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes Blood 2014 124 3719 29 25331115
Weinstein JS, Lezon-Geyda K, Maksimova Y, Craft S, Zhang Y, Su M, et al. Global transcriptome analysis and enhancer landscape of human primary T follicular helper and T effector lymphocytes. Blood. 2014;124:3719–29. 10.1182/blood-2014-06-58270025331115
78. Isoda T Moore AJ He Z Chandra V Aida M Denholtz M Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer-promoter communication and T cell fate Cell 2017 171 103 119.e118 28938112
Isoda T, Moore AJ, He Z, Chandra V, Aida M, Denholtz M, et al. Non-coding transcription instructs chromatin folding and compartmentalization to dictate enhancer-promoter communication and T cell fate. Cell. 2017;171:103–119.e118. 10.1016/j.cell.2017.09.00128938112
79. Liang HC Costanza M Prutsch N Zimmerman MW Gurnhofer E Montes-Mojarro IA Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma Nat Commun 2021 12 5577 34552066
Liang HC, Costanza M, Prutsch N, Zimmerman MW, Gurnhofer E, Montes-Mojarro IA, et al. Super-enhancer-based identification of a BATF3/IL-2R-module reveals vulnerabilities in anaplastic large cell lymphoma. Nat Commun. 2021;12:5577 10.1038/s41467-021-25379-934552066
80. Zhou J Toh SH Tan TK Balan K Lim JQ Tan TZ Super-enhancer-driven TOX2 mediates oncogenesis in natural killer/T cell lymphoma Mol Cancer 2023 22 69 37032358
Zhou J, Toh SH, Tan TK, Balan K, Lim JQ, Tan TZ, et al. Super-enhancer-driven TOX2 mediates oncogenesis in natural killer/T cell lymphoma. Mol Cancer. 2023;22:69 10.1186/s12943-023-01767-137032358
81. Spiro C Li JP Bestwick RK Kabat D An enhancer sequence instability that diversifies the cell repertoire for expression of a murine leukemia virus Virology 1988 164 350 61 2835856
Spiro C, Li JP, Bestwick RK, Kabat D. An enhancer sequence instability that diversifies the cell repertoire for expression of a murine leukemia virus. Virology. 1988;164:350–61. 10.1016/0042-6822(88)90548-x2835856
82. Nakahata S Saito Y Hamasaki M Hidaka T Arai Y Taki T Alteration of enhancer of polycomb 1 at 10p11.2 is one of the genetic events leading to development of adult T-cell leukemia/lymphoma Genes Chromosomes Cancer 2009 48 768 76 19484761
Nakahata S, Saito Y, Hamasaki M, Hidaka T, Arai Y, Taki T, et al. Alteration of enhancer of polycomb 1 at 10p11.2 is one of the genetic events leading to development of adult T-cell leukemia/lymphoma. Genes Chromosomes Cancer. 2009;48:768–76. 10.1002/gcc.2068119484761
83. Maksimova V Smith S Seth J Phelps C Niewiesk S Satou Y HTLV-1 intragenic viral enhancer influences immortalization phenotype in vitro, but is dispensable for persistence and disease development in animal models Front Immunol 2022 13 954077 35958554
Maksimova V, Smith S, Seth J, Phelps C, Niewiesk S, Satou Y, et al. HTLV-1 intragenic viral enhancer influences immortalization phenotype in vitro, but is dispensable for persistence and disease development in animal models. Front Immunol. 2022;13:954077 10.3389/fimmu.2022.95407735958554
84. Matsuo M Ueno T Monde K Sugata K Tan BJY Rahman A Identification and characterization of a novel enhancer in the HTLV-1 proviral genome Nat Commun 2022 13 2405 35504920
Matsuo M, Ueno T, Monde K, Sugata K, Tan BJY, Rahman A, et al. Identification and characterization of a novel enhancer in the HTLV-1 proviral genome. Nat Commun. 2022;13:2405 10.1038/s41467-022-30029-935504920
85. Brightman BK Rein A Trepp DJ Fan H An enhancer variant of Moloney murine leukemia virus defective in leukemogenesis does not generate detectable mink cell focus-inducing virus in vivo Proc Natl Acad Sci USA 1991 88 2264 8 2006167
Brightman BK, Rein A, Trepp DJ, Fan H. An enhancer variant of Moloney murine leukemia virus defective in leukemogenesis does not generate detectable mink cell focus-inducing virus in vivo. Proc Natl Acad Sci USA. 1991;88:2264–8. 10.1073/pnas.88.6.22642006167
86. Hanecak R Pattengale PK Fan H Deletion of a GC-rich region flanking the enhancer element within the long terminal repeat sequences alters the disease specificity of Moloney murine leukemia virus J Virol 1991 65 5357 63 1895389
Hanecak R, Pattengale PK, Fan H. Deletion of a GC-rich region flanking the enhancer element within the long terminal repeat sequences alters the disease specificity of Moloney murine leukemia virus. J Virol. 1991;65:5357–63. 10.1128/jvi.65.10.5357-5363.19911895389
87. Yuen PH Khang YH Kumar A Szurek PF Maull EA The Moloney murine leukemia virus enhancer and its flanking sequences collaborate to determine virulence in T-cell lymphomagenesis Mol Carcinog 1991 4 72 80 2009136
Yuen PH, Khang YH, Kumar A, Szurek PF, Maull EA. The Moloney murine leukemia virus enhancer and its flanking sequences collaborate to determine virulence in T-cell lymphomagenesis. Mol Carcinog. 1991;4:72–80. 10.1002/mc.29400401112009136
88. Boral AL Okenquist SA Lenz J Identification of the SL3-3 virus enhancer core as a T-lymphoma cell-specific element J Virol 1989 63 76 84 2535754
Boral AL, Okenquist SA, Lenz J. Identification of the SL3-3 virus enhancer core as a T-lymphoma cell-specific element. J Virol. 1989;63:76–84. 10.1128/jvi.63.1.76-84.19892535754
89. Sørensen KD Quintanilla-Martinez L Kunder S Schmidt J Pedersen FS Mutation of all Runx (AML1/core) sites in the enhancer of T-lymphomagenic SL3-3 murine leukemia virus unmasks a significant potential for myeloid leukemia induction and favors enhancer evolution toward induction of other disease patterns J Virol 2004 78 13216 31 15542674
Sørensen KD, Quintanilla-Martinez L, Kunder S, Schmidt J, Pedersen FS. Mutation of all Runx (AML1/core) sites in the enhancer of T-lymphomagenic SL3-3 murine leukemia virus unmasks a significant potential for myeloid leukemia induction and favors enhancer evolution toward induction of other disease patterns. J Virol. 2004;78:13216–31. 10.1128/jvi.78.23.13216-13231.200415542674
90. Tupper JC Chen H Hays EF Bristol GC Yoshimura FK Contributions to transcriptional activity and to viral leukemogenicity made by sequences within and downstream of the MCF13 murine leukemia virus enhancer J Virol 1992 66 7080 8 1331510
Tupper JC, Chen H, Hays EF, Bristol GC, Yoshimura FK. Contributions to transcriptional activity and to viral leukemogenicity made by sequences within and downstream of the MCF13 murine leukemia virus enhancer. J Virol. 1992;66:7080–8. 10.1128/jvi.66.12.7080-7088.19921331510
91. Yoshimura FK Wang T Cankovic M Sequences between the enhancer and promoter in the long terminal repeat affect murine leukemia virus pathogenicity and replication in the thymus J Virol 1999 73 4890 8 10233950
Yoshimura FK, Wang T, Cankovic M. Sequences between the enhancer and promoter in the long terminal repeat affect murine leukemia virus pathogenicity and replication in the thymus. J Virol. 1999;73:4890–8. 10.1128/jvi.73.6.4890-4898.199910233950
92. Yoshimura FK Wang T Role of the LTR region between the enhancer and promoter in mink cell focus-forming murine leukemia virus pathogenesis Virology 2001 283 121 31 11312668
Yoshimura FK, Wang T. Role of the LTR region between the enhancer and promoter in mink cell focus-forming murine leukemia virus pathogenesis. Virology. 2001;283:121–31. 10.1006/viro.2001.087911312668
93. Granger SW Bundy LM Fan H Tandemization of a subregion of the enhancer sequences from SRS 19-6 murine leukemia virus associated with T-lymphoid but not other leukemias J Virol 1999 73 7175 84 10438804
Granger SW, Bundy LM, Fan H. Tandemization of a subregion of the enhancer sequences from SRS 19-6 murine leukemia virus associated with T-lymphoid but not other leukemias. J Virol. 1999;73:7175–84. 10.1128/jvi.73.9.7175-7184.199910438804
94. Roderick JE Tesell J Shultz LD Brehm MA Greiner DL Harris MH c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells Blood 2014 123 1040 50 24394663
Roderick JE, Tesell J, Shultz LD, Brehm MA, Greiner DL, Harris MH, et al. c-Myc inhibition prevents leukemia initiation in mice and impairs the growth of relapsed and induction failure pediatric T-ALL cells. Blood. 2014;123:1040–50. 10.1182/blood-2013-08-52269824394663
95. Vanden Bempt M Demeyer S Broux M De Bie J Bornschein S Mentens N Cooperative enhancer activation by TLX1 and STAT5 drives development of NUP214-ABL1/TLX1-positive T cell acute lymphoblastic leukemia Cancer Cell 2018 34 271 285.e277 30107177
Vanden Bempt M, Demeyer S, Broux M, De Bie J, Bornschein S, Mentens N, et al. Cooperative enhancer activation by TLX1 and STAT5 drives development of NUP214-ABL1/TLX1-positive T cell acute lymphoblastic leukemia. Cancer Cell. 2018;34:271–285.e277. 10.1016/j.ccell.2018.07.00730107177
96. Andrieu GP Kohn M Simonin M Smith CL Cieslak A Dourthe M PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL Blood 2021 138 1855 69 34125178
Andrieu GP, Kohn M, Simonin M, Smith CL, Cieslak A, Dourthe M, et al. PRC2 loss of function confers a targetable vulnerability to BET proteins in T-ALL. Blood. 2021;138:1855–69. 10.1182/blood.202001008134125178
