
==== Front
Blood Sci
Blood Sci
BS9
Blood Science
2543-6368
Lippincott Williams & Wilkins Hagerstown, MD

BLS-24-002
00007
10.1097/BS9.0000000000000205
3
Review Article
Mitochondrial genetic variations in leukemia: a comprehensive overview
Zhang Ao ab
Liu Wenbing ab
Qiu Shaowei ab*
a State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
b Tianjin Institutes of Health Science, Tianjin, China
*Address correspondence: Shaowei Qiu, State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, China. E-mail address: qiushaowei@ihcams.ac.cn (S. Qiu).
05 9 2024
10 2024
6 4 e00205e00205
5 1 2024
13 8 2024
Copyright © 2024 The Authors. Published by Wolters Kluwer Health Inc., on behalf of the Chinese Medical Association (CMA) and Institute of Hematology, Chinese Academy of Medical Sciences & Peking Union Medical College (IHCAMS).
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Leukemias are a group of heterogeneous hematological malignancies driven by diverse genetic variations, and the advent of genomic sequencing technologies facilitates the investigation of genetic abnormalities in leukemia. However, these sequencing-based studies mainly focus on nuclear DNAs. Increasing evidence indicates that mitochondrial dysfunction is an important mechanism of leukemia pathogenesis, which is closely related to the mitochondrial genome variations. Here, we provide an overview of current research progress concerning mitochondrial genetic variations in leukemia, encompassing gene mutations and copy number variations. We also summarize currently accessible mitochondrial DNA (mtDNA) sequencing methods. Notably, somatic mtDNA mutations may serve as natural genetic barcodes for lineage tracing and longitudinal assessment of clonal dynamics. Collectively, these findings enhance our understanding of leukemia pathogenesis and foster the identification of novel therapeutic targets and interventions.

Leukemia
mtDNA copy number variations
mtDNA mutations
mtDNA sequencing
Natural genetic barcodes
Prognostic marker
OPEN-ACCESSTRUE
==== Body
pmc1. INTRODUCTION

Leukemias are a group of heterogeneous hematological malignancies resulting from uncontrolled neoplastic proliferation of undifferentiated or partially differentiated hematopoietic cells.1 The occurrence of leukemia cells is closely associated with genetic variations. In addition, the genetic heterogeneity and clonal dynamics of leukemia have been extensively described based on somatic nuclear mutations during disease progression.2–4 However, in addition to these nuclear genetic changes, non-chromosomal mitochondrial genetic variations also play a crucial role in the progression of leukemia.5–8

Mitochondria are the main energy-producing organelles of cells and are also involved in numerous cellular processes including calcium homeostasis, apoptosis, fatty acid oxidation, and the generation of metabolic intermediates.9 Mitochondrial DNA (mtDNA) is a 16 kb double-stranded circular genome containing 37 genes related to the respiratory chain, including 13 messenger ribonucleic acids (mRNAs), 2 ribosomal RNAs (rRNAs), and 22 transfer RNAs (tRNAs) necessary for mitochondrial protein synthesis.7 The mitochondrial genome also includes a noncoding displacement region (D-loop), which has a very significant transcriptional regulation function.10 Unlike the nuclear genome, the mitochondrial genome has no intron (only composed of encoding genes and regulatory sequences), thus one point mutation may cause alterations of important structural genes, leading to changes in expression or property of the expressed proteins.11 Damages easily occur to mtDNA due to its vulnerability without histone protection and a DNA repair system.11 Moreover, mtDNA has a 10-fold higher mutation rate compared to the nuclear genome. Hence, mtDNA incrementally accumulates unique, irreversible genetic mutations and passes on to daughter cells even in healthy humans, which could be used for lineage tracing.12–14 Importantly, the number of mitochondria (and therefore mtDNA) ranges from several hundred to >10,000 per cell in different cell types, facilitating robust mtDNA analysis even from a single cell14 (Table 1).

Table 1 Comparison between the nuclear and mitochondrial genomes.

Characteristic	Nuclear genome	Mitochondrial genome	
Size	~3.3 × 109 bp	16,569 bp	
Number of genes encoded	~20,000–30,000	37	
Number of DNA molecules per cell	46	~100–>10,000	
Gene density	~1 per 40,000 bp	1 per 450 bp	
Introns	Frequently found	Absent	
Percentage of the coding DNA	~3%	~93%	
Histone proteins and DNA repair system	With	Without	
Mode of inheritance	Mendelian inheritance and paternal inheritance	Matrilineal inheritance	

The mtDNA variations encompass mtDNA copy number variations and mutations. Mutations in mtDNA are primarily responsible for mitochondrial abnormalities.15 De novo mutations act as “inducers” of carcinogenesis, while functional variants act as “adaptors,” and enable cancer cells to thrive in diverse environments. The mechanisms through which mtDNA mutations contribute to tumorigenesis involve the modulation of mitochondrial reactive oxygen species production, redox state, and mitochondrial intermediates that act as substrates for chromatin-modifying enzymes. In addition, alterations in the mtDNA can impact mitochondrial metabolites, subsequently influencing the epigenome and nuclear DNA gene expression.16 Some mtDNA mutations exist heteroplasmically, meaning that individual cells contain a mixture of mitochondria with mutant or wild-type (WT) mtDNA. In heteroplasmic cells, the phenotype of a pathogenic mtDNA mutation is determined by the ratio of mutant and WT genomes.17 mtDNA copy number refers to the number of mitochondrial genome copies per nucleated cell. The most common approach to measuring mtDNA copy number is to calculate the ratio of the number of mtDNA copies and nDNA reads (2 copies per cell).18 mtDNA copy number alterations can impact oxidative phosphorylation and energy metabolism, thereby contributing to mitochondrial dysfunction.19,20 It is noteworthy that alterations in mitochondria number per cell are associated with the development of leukemia through the deregulation of respiratory profiles.21

In this review, we aimed to provide a comprehensive overview of mitochondrial genetic variations in leukemia, focusing on mtDNA mutations, copy number variations, mtDNA sequencing methods, and their significance as natural genetic barcodes and prognostic markers. It aims to facilitate the identification of potential therapeutic targets for the treatment of this hematological malignancy (Fig. 1).

Figure 1. The mtDNA abnormalities encompass mtDNA copy number variations and mutations. The mtDNA abnormalities can serve as natural genetic barcodes and prognostic markers in leukemia. Increasing evidence indicates that mitochondrial genome abnormalities are important mechanisms of leukemia pathogenesis. mtDNA = mitochondrial DNA.

2. mtDNA MUTATIONS IN LEUKEMIA

Mitochondria are under a double genetic control carried out by mtDNA and nuclear DNA. mtDNA mutations play critical roles in the reprogramming of mitochondrial metabolism. Studies have revealed that disruptive mutations of mtDNA are typically rare in normal cells but undergo a positive selection in cancer tissues, highlighting the critical role of mtDNA in tumorigenesis.22 This observation has also been confirmed in leukemia since several mutations in mtDNA are associated with leukemia. For instance, Penter et al4 discovered that chronic lymphocytic leukemia (CLL) cells carry at least 1 mtDNA mutation in over 50% of cells and can accumulate numerous additional mutations. He et al23 demonstrated that somatic mtDNA mutations were present in approximately 40% of patients, with the A15296G mutation serving as a leukemia-specific marker. Furthermore, a study identified 2 mitochondrial protein-coding genes (ND6 and Cytb), with mutation frequencies exceeding 5% in platelets from leukemia patients. In particular, the ND6 gene exhibited the highest mutation frequency at 32.65%.11 Recurrent variations at position T489C within the mtDNA D-Loop have been reported in various malignancies.24–26 Tyagi et al10 investigating pediatric acute myeloid leukemia (AML) cases, suggested that the T489C position might be a hotspot for recurrent variations associated with relapse, although these variations occur within the noncoding regions and appear functionally silent, they could potentially impact respiratory chain polypeptide levels and alter electron transport chain (ETC) activity and cellular energy capacity. Some somatic mutations were detected in both diagnosis and remission samples, probably due to the persistence of residual leukemia cells.27

In AML cases specifically, the most observed mtDNA sequence variants were single nucleotide substitutions which might have affected the binding of mtDNA to transcription factors, resulting in abnormal formation of protein complexes, thereby altering normal expression patterns.28 Studies have demonstrated that patients with AML having high expression of mitochondrial transcription machinery (MTM) genes exhibit a significantly short median overall survival (OS; HR = 1.82, P = .003),29 which might be explained by the deregulation of the MTM genes which may also influence the expression of mitochondrial genes and contribute to the pathogenesis of AML. In addition, some studies revealed a mutually exclusive relationship between somatic mitochondrial mutations and the CBFB::MYH11 fusion gene in the beat AML cohort,30 indicating potential substitutable functional mutations31 and deducing that the CBFB::MYH11 fusion gene was probably involved in mitochondrial metabolism reprogramming in AML. Additionally, alterations in copy number variations could co-occur with changes in mtDNA mutations and chromatin accessibility.4 Moreover, some results indicate the congruence of mutations between mtDNA and RNA in AML.30

Mitochondrial mutation rates and the occurrence of leukemia are positively correlated.32 However, the specific mechanism by which mtDNA mutations promote the pathogenesis of leukemia remains unknown. Whether accumulated mutated mtDNA is a consequence of rapid cell division, or if these mtDNA mutations confer selective advantages to transformed cells that contribute to leukemia progression and metastasis, such as affecting mitochondrial metabolism in that cell lineage remains controversial.

3. mtDNA COPY NUMBER VARIATIONS IN LEUKEMIA

Tumor cells display metabolic adaptations by modulating mitochondrial metabolism, ETC complex activities, and mtDNA copy numbers.33 Transcriptional profile analysis has shown close correlations between transcript levels of enzymes of the tricarboxylic acid cycle and ETC, fatty acid β-oxidation, and branched-chain amino acid catabolism pathways with mtDNA copy numbers. Variations in mitochondria copy number reflect the cumulative effects of gene–environmental interactions, and the copy number has been implicated as a potential biomarker for various cancers.7,34,35 Alterations in mtDNA copy number differ between certain tumor types. Studies have shown that the mean mtDNA copy number increased approximately 9-fold in patients with AML compared to that in controls (P < .0001). Pereira-Martins et al36 demonstrated that patients with acute promyelocytic leukemia (APL) treated with chemotherapy and all-transretinoic acid whose leukemia cells had increased mtDNA content had a significantly low cumulative incidence of relapse. Another study suggested that mtDNA copy number was associated with anemia in hematologic malignancies, while red blood cell-bound mtDNA was negatively correlated with hemoglobin levels in patients.37 mtDNA copy number is regulated by various mitochondrial biogenesis genes like TFAM, POLG, and POLRMT. Enhanced mitochondrial biogenesis is an important cellular adaptation in pediatric AML blasts, with a possible impact on disease biology and outcomes.38 A recent study on adults with AML also reported increased expression of TFAM and POLRMT and other mitochondrial transcriptional factor genes like TFB1M and TFB2M, with poor prognostic significance.29

However, further investigation is needed to explore the relationship between mtDNA copy number variations and the pathophysiology and prognosis of leukemia. In some tumors, changes in mtDNA copy number might be an adaptive response secondary to mutations conferring growth advantage for certain tumor types. Furthermore, even within a class of tumors, differences in mtDNA content can correlate with cancer severity,16 although these conclusions have not yet been confirmed in leukemia.

4. TECHNIQUES FOR mtDNA SEQUENCING

Currently, accessible techniques for sequencing mtDNA include the assay for transposase-accessible chromatin sequencing (ATAC-seq), RNA sequencing (RNA-seq), whole genome sequencing, quantitative real-time polymerase chain reaction (PCR), digital PCR, and others. However, since bulk sequencing entangles information from various cell types and obscures cellular heterogeneity, single-cell multi-omics has rapidly progressed.39

Longitudinal tracking of distinct clones within heterogeneous cell populations and linking clonal lineages to specific functional states at the single-cell level has been the focus of numerous endeavors aimed at comprehending disease evolution and mechanisms leading to therapeutic resistance in a wide range of cancers. The advent of genomic techniques has provided the means to concomitantly assess cell types and states with mtDNA genotypes.40 It is worth mentioning that the combination of single-cell transcriptomics with mtDNA mutation detection could also establish lineage relationships.41 Mitochondrial single-cell ATAC-seq (mtscATAC-seq) has emerged as one of the most successful single-cell sequencing methods in its ability to concomitantly profile accessible chromatin profiles alongside mitochondrial genotypes in a scalable manner.42 However, characterizing and interpreting heterogeneous mixtures at the cellular level (also known as cell-type deconvolution) is also of great interest. Single-cell assays offer an opportunity for assigning single cells to the subpopulations (ie, clustering) and de-convolving the bulk data into subpopulation-specific data.43 Other common deconvolution models are listed in Table 2.

Table 2 Summary of the current deconvolution models in ATAC-Seq data.

Deconvolution models	Key references	
DC3	Zeng et al43	
scAVENGERS	Han et al44	
scDeconv	Liu45	
DeconPeaker	Li et al46	
Cellformer	Berson et al47	
DECODER	Peng et al48	
ConDecon	Aubin et al49	
ATAC-Seq = assay for transposase-accessible chromatin sequencing.

5. mtDNA MUTATIONS AS NATURAL GENETIC BARCODES FOR LONGITUDINAL ASSESSMENT

Researchers have demonstrated the utility of somatic mtDNA mutations as natural genetic barcodes that may be stably propagated across cell divisions.14,50 Cells sharing the same mitochondrial mutations are inferred to have descended from the same ancestral cell.14 This offers opportunities for lineage tracing with enhanced resolution within cell populations defined by the same set of somatic mutations or even in the absence of such genetic events.51 Compared to somatic nuclear mutations, mtDNA mutations possess several advantages. Mitochondria can replicate independently of the cell cycle, and mtDNA presents in hundreds of copies per cell. In combination with the small size, mtDNA can therefore be sequenced with high coverage at single-cell resolution without requiring additional targeted amplification steps while simultaneously providing information on cell states.4,9,52 Somatic mtDNA mutations with levels as low as 5% heteroplasmy can be stably propagated, suggesting that even low-frequency heteroplasmic mtDNA mutations can be exploited for lineage tracing. Lineage tracing by mtDNA mutations is highly scalable and combined with assays to profile a cell’s state at the chromatin or transcriptome level. In contrast, detecting nuclear somatic mutations by whole genome sequencing in individual cells remains costly, challenging to implement on a large scale, and prone to substantial error rates.50 In addition, nuclear mutations are often sparse events and frequently subject to selective pressures which could confound the inferences.

Stable propagation of mtDNA mutations over years in the absence of strong selective pressure indicates clonal persistence, but dramatic changes happen following tight bottlenecks including disease transformation and relapse post-therapy, paralleled by acquisition of copy number variants, alterations in chromatin accessibility, and gene expression. mtDNA mutations thus mirror disease history and provide natural genetic barcodes to enable patient-specific study of cancer subclonal dynamics.4 Additionally, some scholars suggest that mtDNA mutations might be markers of a diverging subclone that emerged within the relapse population. They also observed distinct patterns over time for each mutation type, linking subclonal structures to different functional states.4 One study utilizing mtsc ATAC-seq revealed that all the mtDNA mutation subclones were detected in different cell lineage clusters, suggesting multiple cell clones might contribute to the AML hierarchy, and different cells might fall into a similar type of “attractor” in AML.53,54 Additionally, it was found the same phenotype contained multiple clones, implying there were certain key attractors responsible for determining the switching between different states.54,55

Overall, in one validation experiment, mitochondrial genotypes accurately inferred clonal lineage with >95% accuracy, achieving similar accuracy as widely applied genetic labeling methods. However, potential limitations include the horizontal transfer of mitochondria between cells under specific contexts and our incapacity to account for the phenotypic effects of the mtDNA mutations used for clonal tracing.50 Lastly, the bulk nature and relative rarity of mtDNA transcriptome/genome coverage limit confident detection of low-frequency variants, which appeals to complementary bulk and single-cell genotyping assays optimized for mtDNA sequence capture.40 Enhanced throughout and expanded coverage of single cells in the future will augment the level of detection of mtDNA mutations, thereby facilitating the tracking of clones using mtDNA mutations in settings such as premalignant states or minimal residual disease.4 Applications of these methodologies also include the study of acquired therapeutic resistance and efficient tracking of donor and recipient chimerism during hematopoietic stem cell transplant.50 Moreover, it is crucial to emphasize the integration of capturing mtDNA mutations with different types of nuclear mutations, which would further enhance the elucidation of both genomic and non-genomic evolution of malignant cells.4

6. mtDNA VARIATIONS AS A PROGNOSTIC MARKER IN LEUKEMIA

Mitochondria have a functional role in leukemia, numerous studies have reported that mtDNA variations may serve as a prognostic marker. mtDNA mutations in patients with AML were associated with inferior disease-free survival.56 mtDNA copy number was often increased with a negative impact on disease aggressiveness and inferior survival in pediatric acute leukemia.7,33 Mitochondrial heteroplasmic single nucleotide variants were also linked with prognosis in leukemia.57 Mutations in mitochondrial genes that encode complexes I, III, and IV of the ETC have been linked to worst outcomes in patients with AML, potentially providing targets for therapeutic intervention.58,59 Nicotinamide adenine dinucleotide hydrogen dehydrogenase subunit 4 (ND4) is a mitochondrial encoded transmembrane component of the ETC respiratory complex I, patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P = .017) and OS (P = .021) than those with ND4 (WT),60 which implied the favorable prognostic influence of acquired ND4 mutations in AML. Variations in one of the hypervariable regions in the D-Loop region (HV-1), namely 16126T-->C (P = .05), 16224T-->C (P < .01), and 16311T-->C (P < .001), were significantly associated with the inferior encrypting file system in pediatric AML.61 Studies also found a strong association between deleterious heteroplasmic mitochondrial mutations and mortality.57 However, some studies indicated that the impact of mtDNA copy number on outcomes in adult AML showed no significant association with survival,7 further investigations should be conducted to examine this question.

7. CONCLUSION

mtDNA encodes critical components for mitochondrial function. Mitochondrial dysfunction caused by mtDNA mutations and copy number variations is closely implicated in tumorigenesis and progression.62 Mitochondrial genetic analysis can enhance the stratification of malignant cells and improve our understanding of clonal dynamics in response to therapies, including putative treatment-sensitive and resistant clones.40,50 However, how we can effectively and longitudinally study clonal dynamics in humans remains an important question. A systematic understanding of somatic mitochondrial variations and their interplay with the nuclear genome in leukemia remains poorly understood.

Conflict of interest: The authors declare that they have no conflict of interest.
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