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N6-methyladenosine (m6A) RNA Modification’s Regulatory Role in Acute and Chronic Leukemia

  • Ziba Majidi1 ,
  • Pariya Mohammadyari2 ,
  • Zahra Kashani Khatib2  and
  • Shaban Alizadeh2,* 
Gene Expression   2024

doi: 10.14218/GE.2024.00030

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Citation: Majidi Z, Mohammadyari P, Kashani Khatib Z, Alizadeh S. N6-methyladenosine (m6A) RNA Modification’s Regulatory Role in Acute and Chronic Leukemia. Gene Expr. Published online: Aug 2, 2024. doi: 10.14218/GE.2024.00030.

Abstract

Hematological malignancies present a complex challenge within oncology, necessitating a thorough understanding of genetic factors for effective detection and management. As we delved into the forefront of cancer research, our focus turned to the emerging field of N6-methyladenosine (m6A) epigenetic approaches. Among RNA modifications, m6A is the most common and thoroughly investigated post-transcriptional alteration in messenger RNA. The m6A modification involves the addition of a methyl group to the adenosine at the N6 position within RNA molecules, a process mediated by proteins collectively referred to as m6A writers, erasers, and readers. The dynamic nature of m6A modifications on RNA molecules presents a promising avenue for enhancing our understanding of gene expression regulation in hematological malignancies. This review explores the potential breakthroughs that m6A epigenetic tools offer in cancer diagnostics and treatment, highlighting their role in enabling more precise interventions. By acknowledging the importance of genetic insights and integrating advancements in m6A epigenetics, this article advocates for a comprehensive approach to managing hematological malignancies.

Keywords

Hematological malignancies, Leukemia, N6-methyladenosine (m6A), Epigenetics, RNA modification, Cancer diagnostics

Introduction

Today, epigenetics, which entails the modification of chromosomes without altering DNA sequences, serves as a crucial regulatory mechanism for gene expression. Hence, “epigenetic” modifications extend to various RNA types, including ribosomal RNA, transfer RNA, small nuclear RNA, and messenger RNA (mRNA), collectively referred to as “epitranscriptomics”.1 Since the discovery of the first RNA pseudouridine modification, referred to as the “fifth nucleotide”, in 1957, over 170 distinct chemical modifications have been identified in both protein-coding and non-protein-coding RNA transcripts.2 Among these modifications, N6-methyladenosine (m6A) is the most common and well-studied post-transcriptional modification in mRNA. m6A RNA modification involves the methylation of adenosine at the N6 position within RNA molecules. This process is facilitated by a group of proteins known as m6A writers, erasers, and readers (Fig. 1), which collectively coordinate a precisely regulated network.3 Recent investigations into various RNA modifications reveal their dynamic involvement across a wide range of pathological and physiological contexts, including normal development and malignant transformation. Specifically, evidence indicates that RNA modifications play an important role in normal hematopoiesis, especially myelopoiesis, and in the onset and progression of leukemia.4,5 Additionally, other modifications such as 5-hydroxymethylcytosine, 5-methylcytosine, adenosine to inosine editing, and pseudouridine also play roles in normal hematopoiesis and/or leukemogenesis.6,7

The roles of m6A RNA modification in leukemia.
Fig. 1  The roles of m6A RNA modification in leukemia.

The m6A RNA modification involves three key actors: writers, erasers, and readers. Writers, including m6A methyltransferases such as METTL3, METTL14, and WTAP, add methyl groups to RNA. Erasers, such as ALKBH5 and FTO, are responsible for removing methyl groups from RNA molecules. Readers, which are proteins that recognize m6A sites, play various roles including RNA splicing, microRNA processing, translation, and RNA degradation. Some of these readers include YTHDC1, IGF2BPs and HNRP C are usually found in the nucleus while YTHDF1, 2, 3, and YTHDC2 are cytoplasmic. Dysregulation of these proteins and m6A levels can contribute to hematological malignancies. A, adenosine; ALKBH5, AlkB homolog 5; FTO, fat mass and obesity-associated; HNRP, heterogeneous nuclear ribonucleoprotein; IGF2BPs, insulin-like growth factor-2 mRNA-binding protein; m6A, N6-methyladenosine; METTL3, methyltransferase-like 3; WTAP, Wilms’ tumor 1-associated protein; YTHDC1, YTH domain-containing protein 1; YTHDF1, YTH N6-methyladenosine RNA binding protein 1.

A diverse set of chemical modifications found in RNA are necessary for regulating gene expression. These modifications contribute to pre-mRNA processing and expression in the nucleus, as well as to mRNA translation and processing, highlighting their broad impact on RNA biology. The m6A modification acts as a key post-transcriptional regulatory mechanism that influences RNA metabolism and various cellular functions. It modulates processes such as splicing, stability, and translation efficiency, thereby exerting significant control over gene expression. Understanding the complex regulatory mechanisms of m6A is essential to unravel the intricacies of gene regulation in health and disease.8,9

In the context of cancer, including leukemia, RNA modifications such as m6A, 5-methylcytosine, and pseudouridine (Ψ) are recognized as critical post-transcriptional regulators influencing gene activity patterns. The association between m6A modification and cancers further emphasizes its significance in understanding disease mechanisms. Over time, it has been recognized that the development of tumors involves several stages driven by numerous genetic changes, some of which contribute to the progressive transformation of normal cells into a malignant state. In addition to genetic alterations, mounting evidence indicates that epigenetic mechanisms play a significant role in cancer development. Recent studies, particularly in the realm of leukemia, have emphasized the crucial role of the m6A variant as an epigenetic modification in the advancement and progression of both acute and chronic forms of the disease.10–12 The dysregulation of m6A has been implicated in leukemogenesis, influencing the behavior of leukemic stem cells (LSCs) and playing a role in the pathogenesis of leukemia.13,14 Hematologic malignancies are a significant global concern, ranking sixth in cancer incidence worldwide and holding the top position in cancer-related mortality among adolescents.15 It is crucial to explore factors affecting these malignancies through genetic and epigenetic approaches. The future importance of hematologic malignancies is related to several key factors. First, these malignancies, which include various forms of blood cancers such as leukemia, lymphoma, and myeloma, impose a significant burden on global health care. The evolution of our understanding of the molecular and genetic basis of these diseases has led to the development of targeted therapies that improve outcomes. Second, hematological malignancies are often used as models for cancer research. Insights gained from studying these diseases often have broader applications for understanding carcinogenesis, the function of the immune system, and therapeutic strategies applicable to other types of cancers. Additionally, the incidence of hematological malignancies is expected to increase along with the aging of the world population.16,17 Addressing the challenges posed by these diseases requires continuous research, innovative treatments, and a multidisciplinary approach to patient care. In summary, the future importance of hematologic malignancies is multifaceted, including their role in advancing cancer research, their impact on health care, and their increasing significance in an aging population. Epigenetics plays a crucial role in the assessment, prognosis, and management of hematological malignancies, especially in the context of early detection and personalized approaches. Abnormal epigenetic patterns serve as specific markers for various blood cancers, enhancing diagnostic precision and allowing rapid intervention. The potential of epigenetics in predicting disease progression and response to therapy highlights its essential role in improving diagnostic accuracy and treatment efficacy in hematological malignancies.18,19

The primary purpose of this review was to comprehensively elucidate the crucial role of m6A RNA modification in gene expression regulation in both acute and chronic leukemia. This review synthesizes current findings on how m6A modifications impact hematopoiesis and leukemogenesis, detailing the dynamic interactions among m6A writers, erasers, and readers in leukemia. The significance of this review lies in advancing our molecular understanding of leukemia, highlighting the scientific value of targeting m6A-related pathways for therapeutic interventions. Given the mounting evidence linking m6A dysregulation to leukemia progression and resistance to conventional therapies, this review underscores the necessity for ongoing research in this field. Furthermore, the insights provided can pave the way for developing novel diagnostic markers and targeted therapies, addressing the urgent need for more effective and personalized treatments for leukemia patients. By exploring the current landscape and future prospects of m6A RNA modification research, this review contributes to the broader goal of enhancing cancer diagnostics and therapeutic outcomes.

m6A methylation modifications

As we explore the intricate molecular dynamics of epigenetic modification, it becomes evident that m6A methylation plays a multifaceted role in the regulation of gene expression, thereby exerting significant effects on diverse pathological and physiological processes. m6A, or N6-methyladenosine, is a common RNA modification that involves the addition of a methyl group to the adenosine base at the nitrogen-6 position. This modification occurs mainly in mRNA molecules but is also present in various other RNA types, including long non-coding RNA (lncRNA) and microRNA. Writers are enzymes responsible for m6A modifications, erasers are tasked with removing these modifications, and readers are responsible for interpreting the modified RNA.20,21

The core constituents of the m6A methyltransferase complex, referred to as the writers, include Wilm’s tumor 1-associated protein (WTAP), methyltransferase-like 3 (METTL3), and methyltransferase-like 14 (METTL14). These enzymes collaborate to perform m6A modifications on RNA transcripts, marking them for subsequent regulatory processes. The Fat mass and obesity-associated (FTO) and AlkB homolog 5 (ALKBH5) serve as demethylases, tasked with removing m6A modifications. This reversible characteristic of m6A marks provides a dynamic regulatory mechanism for gene expression. Proteins that identify and attach to m6A-modified RNA serve as readers, influencing various aspects of RNA metabolism. The YT521-B homology (YTH) domain family encompasses key components, namely YTH domain family proteins 1/2/3 (YTHDF1/2/3) and YTH domain-containing proteins 1/2 (YTHDC1/2), positioning them as pivotal m6A reader proteins. Notably, YTHDC1 stands out as the only m6A-binding protein in the nucleus, whereas YTHDC2 and YTHDF1-3 are primarily located in the cytoplasm. The YTH domain-containing proteins and eIF3 are prominent examples of m6A readers, participating in processes such as RNA splicing, export, translation, and decay.22–25

The significance of m6A methylation’s functionality can be described as follows: regulation of translation (m6A modifications affect mRNA translation efficiency, impacting the production of specific proteins that are critical for cellular functions); RNA splicing and processing (m6A changes participate in alternative splicing, influencing the variety of mRNA isoforms and contributing to the complexity of the human transcriptome); cellular differentiation and development (m6A methylation is involved in regulating stem cell fate determinations, embryonic development, and tissue-specific gene expression); and disease associations (the disruption of m6A modifications has been associated with various human disorders, including cancer, neurodegenerative conditions, and metabolic disorders).26–31

m6A modification in normal hematopoiesis

The blood system is formed through a process termed hematopoiesis, which follows a cellular hierarchy. Hematopoietic stem cells (HSCs) play a crucial role in this process, distinguished by their ability to self-renew and differentiate into various blood cell types. These HSCs give rise to diverse progenitor cells capable of generating multiple lineages, which then differentiate into lineage-specific precursors and, ultimately, mature blood cells.32 Studies suggest that the function of HSCs is influenced by epigenetic mechanisms, including DNA methylation and histone modification.33 Additionally, the significance of m6A RNA methylation in regulating the functionality of HSCs and the hematopoietic process has also been emphasized.

In the developmental hematopoietic process, m6A plays a role at various stages, including the early phase of hematopoietic stem and progenitor cell (HSPC) formation during embryonic development.34,35 HSPCs originate from hemogenic endothelial (HE) cells through the endothelial-to-hematopoietic transition (EHT).36 Notably, studies conducted by Zhang et al.35 revealed the regulatory role of m6A in the differentiation of HSPCs in zebrafish blood and vascular tissues. The findings showed that m6A influences the gene expression equilibrium of HE cells during EHT. Mechanistically, m6A modification mediates the YTHDF2-dependent degradation of Notch receptor 1α (Notch1α) mRNA, thereby modulating the activity of the Notch signaling pathway. Recent findings suggest that the deletion of METTL3 in vascular endothelial cells significantly suppresses EHT by reducing the m6A methylation modification level of Notch1α mRNA, thus inhibiting HSPC generation. Consequently, m6A is essential for regulating HSPC generation during the hematopoietic process, particularly in the early stages of zebrafish embryogenesis. A comparable phenotype was observed in mouse models with METTL3 knockdown.32,35 Vu et al.37 used short hairpin RNAs to suppress METTL3 levels in HSPCs, resulting in reduced cell growth and increased myeloid differentiation. Conversely, the enhancement of wild-type METTL3, but not the catalytically-dead form, led to increased proliferation and colony formation while inhibiting myeloid differentiation. Like METTL3, METTL14 is a crucial element of the m6A methyltransferase complex (writers) with elevated expression in Lin− Sca-1+c-kit+ cells and murine HSPCs. However, its expression decreases during myelopoiesis, particularly in granulocyte-macrophage progenitors, common myeloid progenitors, and mature myeloid cells. Reducing METTL14 levels in human HSPCs through short hairpin RNAs promotes myeloid differentiation in vitro. Additionally, using a conditional knockout of METTL14 in mice demonstrated that its removal hinders the self-renewal capacity of HSCs.

Recent research employed METTL14 and METTL3 conditional knockout mice to investigate the influence of these m6A writer proteins on the regulation of HSC self-renewal in the bone marrow of adult mice. The study revealed that deleting METTL3 alone or in combination with METTL14 in the hematopoietic system significantly elevates the frequency of HSCs in the bone marrow. However, the deletion of METTL14 alone exerts minimal impact. Notably, the conditional deletion of METTL14, particularly METTL3, impairs HSC self-renewal activity in recipient mice. Furthermore, while the deletion of either METTL3 or METTL14 results in a significant decline in donor-derived myeloid cells in the peripheral blood, only the deletion of METTL3 leads to a significant decrease in B- and T-cell lineages.38

RNA-binding motif protein 15, identified within the m6A methyltransferase complex, contributes to normal hematopoiesis.39–41 It exhibits high expression in murine HSCs but is moderately expressed at other stages of hematopoietic development. Conditional knockout of Rbm15 in mice impedes pro/pre-B differentiation and promotes the expansion of megakaryocytic and myeloid cells. Depletion of Rbm15 leads to a bias toward granulocytic maturation.41 A separate investigation revealed expression of Rbm15 in lineage-depleted bone marrow cells, contrasting with its reduced expression in differentiated megakaryocytes and macrophages. Enforced expression of Rbm15 suppresses myeloid differentiation, indicating that enforced expression refers to the artificial overexpression of Rbm15 in experimental models, leading to the suppression of myeloid differentiation. Rbm15 triggers Notch-induced HES1 transcription in hematopoietic cells, leading to the inhibition of myeloid differentiation.40 Additionally, conditional knockout of Rbm15 hinders the differentiation of long-term HSCs into short-term HSCs and leads to an abnormal increase in megakaryocyte development in mice.39

Studies on YTHDF2 highlight the significance of m6A readers in regulating myelopoiesis. YTHDF2, an m6A reader protein, facilitates the decay of mRNA in its designated transcripts.42 Lack of YTHDF2 in mice leads to the growth of functional HSCs under hematopoietic stress and physiological situations, without inducing abnormal differentiation within cell lineages or hematopoietic malignancies.43,44 Conditional knockout of YTHDF2 in murine HSPCs does not display functional impairments; instead, it enhances repopulating and regenerative capabilities due to the activation of Wnt signaling following YTHDF2 deletion.43

m6A modification in acute leukemia

Acute myeloid leukemia (AML)

AML is an extremely aggressive blood cancer that poses a life-threatening risk without adequate treatment. Despite advancements in risk assessment and therapeutic approaches, the 5-year survival rate for AML patients remains below 30%. There is a critical need for deeper comprehension of the underlying mechanisms of AML progression to develop potential treatments. AML represents the most prevalent form of leukemia in adults, comprising approximately 80% of cases. In the United States, the AML patient population reached 73,168 in 2020, with a yearly age-adjusted incidence rate of 4.3 cases per 100,000 individuals. The incidence of AML increases with age, and the median age at diagnosis is a crucial factor in understanding its prevalence. AML is responsible for about 2% of all cancer-related deaths in the UK, accounting for approximately 2,700 deaths annually.45,46

Recent studies underscore the significance of m6A RNA modification in cancer, particularly in AML progression. This modification profoundly influences the behavior of LSCs and extends beyond AML to various cancers, promoting tumor progression and drug resistance. For example, overexpression of m6A demethylase in relapse samples increases drug resistance in AML cells. Additionally, m6A readers play a role in promoting AML. The m6A methylase participates in various biological processes such as mammalian development, tumor generation, immunity, metastasis, stem cell renewal, and fat differentiation.47–49 Understanding the intricate relationship between m6A and AML offers valuable insights into potential therapeutic targets and prognostic indicators for this hematopoietic malignancy. Identifying the principal regulators of m6A modifications in AML could lead to enhanced therapeutic approaches for patients with this disease.

Recent research has explored the complex connection between m6A writers and the development of AML. METTL3 and METTL14, acting as key “writers”, assume pivotal roles in governing RNA epigenetics. In AML, these writers exert significant influence over various stages of leukemia development.50,51 Enhanced m6A modification, mediated by METTL3, disrupts key genes involved in AML initiation and progression. Additionally, METTL14 and WTAP, another essential m6A writer, show similar implications in AML pathogenesis (Table 1).37,40,52–86 Dysregulation of m6A writers in AML not only reveals molecular mechanisms but also presents potential therapeutic targets. Targeting these m6A writers may provide novel strategies for AML treatment by modulating RNA epigenetic landscapes. As our understanding of the intricate interplay between m6A writers and AML deepens, it opens avenues for developing targeted therapies aimed at disrupting aberrant RNA modifications associated with leukemia. Recent research highlights METTL3’s dual role in cancer. Traditionally known as a methyltransferase contributing to cancer progression through its methyltransferase activity, there is emerging evidence of an additional methyltransferase-independent function of cytoplasmic METTL3. This alternative mechanism is linked to promoting cancer advancement. Notably, METTL3’s cytoplasmic expression, regardless of its methyltransferase activity, plays a significant role in various facets of tumor progression, facilitating tumorigenesis, cell proliferation, invasion, migration, and accelerating the cell cycle. The use of KH12, a potent METTL3 degrader, has shown promise in reducing m6A levels in MOLM-13 cells, leading to anti-AML effects by lowering c-MYC protein levels.87METTL3 contributes to tumor progression by stabilizing lncRNA PSMA3-AS1, a recognized promoter of tumor advancement. PSMA3-AS1 influences FLT3-ITD+ AML by targeting miR-20a-5p, which regulates the expression of ATG16L1, a down-regulated mRNA in AML that impacts disease progression. This study integrates bioinformatics analysis, in vitro, and in vivo experiments to confirm METTL3 and PSMA3-AS1’s regulatory roles in the disease process. Furthermore, METTL3’s role in stabilizing PSMA3-AS1 suggests a potential cause for its increased expression. These findings offer valuable insights, serving as a foundation for tailoring targeted drugs to address FLT3-ITD AML.52METTL3, a methyltransferase-like 3, significantly influences the progression and chemoresistance of AML by impacting bone marrow mesenchymal stem cells (BMMSCs). Research has revealed diminished METTL3 expression in AML BMMSCs. In vivo experiments using mice with METTL3 depletion in BMMSCs showed elevated bone marrow adiposity, accelerated AML advancement, and increased resistance to cytarabine chemotherapy. METTL3 deletion in BMMSCs significantly increased adipogenesis of BMMSCs, linked to m6A-dependent decrease in AKT1 expression, a serine/threonine kinase 1 within the AKT pathway. This process promotes chemoresistance in AML. Targeting METTL3-mediated BMMSC adipogenesis could serve as a therapeutic approach for AML.53 Aberrant expression of circular RNAs (circRNAs) has been shown to influence AML progression. The novel circRNA, Circ_0001187, contributes to poor prognosis by being downregulated in AML patients. Knockdown of Circ_0001187 promotes AML cell proliferation and inhibits apoptosis, while overexpression has the opposite effect. Circ_0001187 reduces mRNA m6A modification by promoting the degradation of METTL3 protein. It acts as a competitive endogenous RNA, sequestering miR-499a-5p to upregulate RNF113A expression, which mediates METTL3 ubiquitin/proteasome-dependent degradation. Additionally, low Circ_0001187 expression is influenced by histone acetylation and promoter DNA methylation. These results indicate that Circ_0001187 acts as a crucial tumor suppressor in AML via the miR-499a-5p/RNF113A/METTL3 axis.54 In one study, the WTAP-SUCLG2-AS1-miR-17-5p-JAK1 pathway was identified as a crucial regulatory mechanism in AML development. Overexpressing SUCLG2-AS1 inhibited AML cell growth, migration, and invasion while enhancing apoptosis. SUCLG2-AS1 acts as a competitive endogenous RNA by sponging miR-17-5p, resulting in underexpression of JAK1. Additionally, WTAP was found to regulate m6A RNA methylation on SUCLG2-AS1 within AML cells, with increased WTAP levels linked to poor prognosis.55 Another study focused on hypoxia-inducible factor 1α (HIF1α) in t(8;21) AML. They found that HIF1α, known for its abnormal overexpression in this type of leukemia, acts as an oncogene by stimulating the expression of WTAP. WTAP overexpression alters the distribution of m6A on a transcriptome-wide scale, contributing to enhanced cell proliferation in this leukemia subtype. Research also revealed that elevated WTAP expression is linked to adverse prognosis in t(8;21) AML patients. Silencing WTAP hindered leukemia cell proliferation, triggered apoptosis, and facilitated cell differentiation. Mechanistically, HIF1α was found to activate WTAP transcription by directly binding to the hypoxia-response element in the gene’s promoter region. Targeting the HIF1α-WTAP axis, either pharmacologically or genetically, led to a reduction in m6A levels within the transcript of lysine demethylase 4B (KDM4B). This resulted in enhanced degradation of KDM4B, associated with reduced KDM4B expression and elevated levels of trimethylation of histone H3 at lysine 9. Suppression of KDM4B inhibited the growth of leukemia cells both in cell cultures and in murine models. In summary, the study emphasizes that HIF1α-mediated elevation of WTAP amplifies the malignant characteristics of leukemia cells. Moreover, it establishes a connection between m6A RNA methylation and histone methylation, demonstrating how the HIF1α-WTAP pathway influences the translation of m6A-dependent KDM4B, thereby affecting the overall development of t(8;21) AML.56

Table 1

m6A modification in acute leukemia (AML & ALL)

Cancer typem6A modifiersRegulation/Role in cancerBiological functionsMechanismsPotential clinical applicationRef
AMLMETTL3OncogeneMETTL3 has the potential to enhance the stability of PSMA3-AS1 RNA. PSMA3-AS1 might contribute to the progression of FLT3-ITD+ AML by regulating autophagy levels through the miR-20a-5p/ATG16L1 pathway.METTL3/PSMA3-AS1/miR-20a-5p/FLT3-ITD+
PSMA3-AS1/FLT3-ITD+
miR-20a-5p/ATG16L1		Prompt screening and tailored therapy of FLT3-ITD+ AML52
AMLMETTL3OncogeneThe downregulation of AKT1 expression in BMMSCs leads to a significant increase in adipogenesis. This downregulation occurs in an m6A-dependent manner, highlighting the role of m6A modification in modulating AKT1 levels.METTL3/AKT1Targeting METTL3 modification as a therapeutic strategy in AML patient53
AMLMETTL3OncogeneCirc_0001187 diminishes mRNA m6A modification levels in AML cells by degrading the METTL3 protein.miR-499a-5p/RNF113A/METTL3Potential therapeutic targeting of Circ _0001187 as a tumor suppressor in AML patient54
AMLMETTL3OncogeneMETTL3 was increased in AML cells, leading to induction of cell proliferation and inhibition of cell differentiation.METTL3/c-MYC/BCL2/PTENTherapeutic targeting of METTL3 in AML37
AMLMETTL3OncogeneMETTL3 induces proliferation and suppresses differentiation in AML cells. Downregulation of METTL3 leads to cell cycle arrest and causes leukemia cells to differentiate.CEBPZ/METTL3/SP1Potential therapeutic target for AML77
AMLMETTL14OncogeneMETTL14 can suppress the differentiation of normal myeloid cells and is essential for the progress and maintenance of AML via m6A modifications.SPI1-METTL14- MYB/MYCTargeting METTL14 as an effective therapeutic method to treat METTL14-high AMLs78
AMLWTAPOncogeneThe expression of WTAP is increased in AML patients and its overexpression can be correlated with poor prognosis.WTAP/SUCLG2-AS1/miR-17-5p/JAK1Novel therapeutic target for AML treatment55
AMLWTAPOncogeneHIF1α promotes the expression of WTAP which markedly alters the transcriptome-wide m6A distribution and enhances cell proliferation in AML. WTAP is overexpressed and predicts poor prognosis in AML patients.HIF1α/WTAP–56
AMLWTAPOncogeneWTAP promotes cell proliferation, tumorigenesis, and chemoresistance of AML.WTAP/MYCNovel prognostic marker and new treatment target for AML patient79
AMLWTAPOncogenemiR-550-1 can suppress tumor progression that is downregulated in AML. miR-550-1 reduces the WWTR1 stability by the reduction in m6A levels through targeting WTAP.miR-550-1/WTAP/WWTR1/BCL-2
miR-550-1/WTAP/WWTR1/CDK6/Rb/E2F1		Upregulation of miR-550-1 can be used as a valuable therapeutic strategy in AML80
AMLWTAPOncogeneWTAP is upregulated in AML cells due to both decrease and increase of METTL3, which has oncogenic function only in the presence of METTL3.METTL3/WTAP–81
AMLWTAPOncogeneWTAP promotes cell proliferation and chemoresistance and inhibits differentiationNot availableA promising therapeutic target in AML82
AMLFTOOncogeneElevated FTO expression in relapse samples contributes to drug resistance in AML cells both in vivo and in vitroFTO/FOXO3Potential therapeutic target of the FTO-m6A-FOXO3 axis in AML patients63
AMLFTOOncogeneFTO is overexpressed in t(8;21) AML, which is positively linked with AML1-ETO. Furthermore, FTO induces the expression of AML1-ETO by suppressing YTHDF2-mediated AML1-ETO mRNA decay. Deletion of FTO significantly inhibits cell proliferation, enhances cell differentiation, and contributes to chemoresistance.AML1-ETO/FTO/IGFBP2Therapeutic target of AML1-ETO/FTO/IGFBP2 pathway in t(8;21) patients with resistance to Ara-C64
AMLFTOOncogeneBM-MSCs-isolated exosomes transport FTO, thereby enhancing the cancer aggressiveness, stem cell characteristics, and resistance to Cytosine arabinoside (Ara-C) chemotherapy in AML cells.BM-MSCs-derived FTO-exo/lncRNA GLCC1/IGF2BP1/c-MycPotential biomarkers for the diagnosis and therapy of AML patients65
AMLFTOOncogeneSsD suppresses AML cell proliferation and induces apoptosis and cell cycle arrest by targeting FTO/m6A signaling.Not availableTherapeutic targeting of FTO/m6A and the clinical potential of Saikosaponin in AML patients57
AMLFTOOncogeneFTO is highly expressed in AML and reduces m6A levels in ASB2 and RARA mRNA, thereby promoting leukemic oncogene-mediated cell transformation and leukemogenesis, and suppressing all-trans-retinoic acid (ATRA)-induced AML cell differentiation.FTO/ASB2, RARAA promising therapeutic strategy by targeting FTO to treat leukemia58
AMLFTOOncogeneR-2HG disrupted the post-transcriptional enhancement of PFKP and LDHB expression (two vital glycolytic genes), mediated by FTO/m6A/YTHDF2, thus reducing aerobic glycolysis in leukemia.FTO/m6A/PFKP/LDHBClinical application of potent FTO inhibitors for cancer therapy59
AMLFTOOncogeneFTO promotes leukemogenesis. FTO inhibitors namely FB23 and FB23-2, suppress proliferation, induce differentiation, and promote apoptosis in human AML cells.Not availableTherapeutic targeting FTO by small-molecule inhibitors for potential treatment of AML60
AMLALKBH5OncogeneALKBH5 is regulated by chromatin state alteration during leukemogenesis of AML and is required for maintaining LSC function and tumor development.KDM4C, MYB, Pol II/ALKBH5/AXLThe therapeutic target of ALKBH5 for specific targeting LSCs61
AMLALKBH5OncogeneThe expression of ALKBH5 is increased in AML which correlates with poor prognosis. ALKBH5 is essential for the progression and maintenance of AML and self-renewal of leukemia stem/initiating cells (LSCs/LICs).ALKBH5/TACC3The therapeutic potential of targeting ALKBH5/m6A axis for the treatment of AML62
AMLYTHDC1OncogeneYTHDC1 interacted with HOXB-AS3, controlling its expression. Elevated levels of either YTHDC1 or HOXB-AS3 stimulated the growth of THP-1 cells and LSCs while hindering their apoptosis leading to an escalation in the count of LSCs in the blood and bone marrow of AML mice.YTHDC1/HOXB-AS3Novel perspective for treatment of AML patients72
AMLYTHDC1OncogeneYTHDC1 is overexpressed in AML and is involved in the proliferation and survival of AML cells, as well as the self-renewal of leukemia stem cells (LSCs) in miceYTHDC1/MCM4Therapeutic potential of targeting YTHDC1 for the treatment of AML patients83
AMLYTHDC1OncogenenYACs prevent m6A-mRNA degradation by PAXT complex and exosome-related RNAs and also induce mRNA stability, AML cell survival, and undifferentiated state.YTHDC1-m6A condensates (nYACs)–84
AMLYTHDF1OncogeneThe expression of YTHDF1 is increased in human AML samples, particularly in LSC. YTHDF1 facilitates the translation of cyclin E2. Knockdown of YTHDF1 diminishes the self-renewal ability and proliferation of AML cells.YTHDC1/cyclin E2A potential therapeutic target of YTHDF1 for the treatment of patients with AML69
AMLYTHDF2OncogeneThe level of YTHDF2 is overexpressed in AML patients, particularly in relapsed patients, and has a tumorigenic function in AML.YTHDF2/miR-126reduction of YTHDF2 enhances HSC expansion and this makes it an ideal candidate for AML treatment66
AMLYTHDF2OncogeneYTHDF2 expression is increased in t (8; 21)-type AML patients, and knockdown of YTHDF2 inhibits tumor cell proliferation in vitro and in vivo.AML1/ETO-HIF1α loop/YTHDF2/TNFRSF1b–68
AMLYTHDF2OncogeneYTHDF2 is overexpressed in AML patients which contributes to the disease initiation and progression. In addition, YTHDF2 participates in the general integrity of LSCs function.YTHDF2/TNFR2Inhibition of YTHDF2 as a unique therapeutic target to target LSCs and augment HSCs67
AMLIGF2BP1OncogeneIGF2BP1 promotes cell proliferation and chemoresistance and inhibits differentiation in AML cells.IGF2BP1/ALDH1A1, HOXB4, MYBTherapeutic potential of targeting IGF2BP1 for the treatment of AML patients85
AMLIGF2BP2Oncogenelevel of IGF2BP2 is increased in AML, which correlates with a poor prognosis. IGF2BP2 facilitates the progression of AML and enhances the self-renewal capacity of leukemia stem or initiation cells by controlling the expression of crucial targets such as MYC, GPT2, and SLC1A5 involved in glutamine metabolism pathways.IGF2BP2/MYC, GPT2, and SLC1A5The potential of targeting IGF2BP2 as a novel strategy for the treatment of AML patients70
AMLIGF2BP3OncogeneIGF2BP3 is increased in AML and required for the survival of AML cells. Deletion of IGF2BP3 inhibits apoptosis and decreases the proliferation of AML cells in vitro and in vivo.IGF2BP3/RCC2Therapeutic potential of targeting IGF2BP3 for the treatment of AML patients71
AMLYBX1/IGF2BPsOncogeneYBX1 expression level is upregulated in myeloid leukemia cells, which maintains AML cell survival. YBX1 deficiency promotes apoptosis and induces differentiation while decreasing the proliferation of AML cells in vitro and in vivo. Furthermore, YBX1 through interacting with IGF2BPs maintains m6A-modified RNA.YBX1/MYC/BCL2 (mRNA)The therapeutic targeting of YBX1 in myeloid leukemia86
ALLMETTL3/METTL14–METTL3 and METTL14 reduction indicate a possible role in the pathogenesis and development of E/R-positive pediatric ALL.Not availableNew prognostic factors and targeted therapy in E/R-positive ALL relapse patients73
ALLWriters/ErasersOncogeneElevated mRNA expression level of m6A writers (like METTL3, METTL14, WTAP) and m6A erasers (like FTO and ALKBH5) led to increased disease burden in patients with ALL.Not available–74
ALLALKBH5OncogeneALKBH5 increased USP1 mRNA stability and decreased m6A levels, which led to upregulation of USP1 and further promoted T-ALL development and chemoresistance.ALKBH5/USP1/Aurora BPotential biomarker for the chemoresistance treatment of T-ALL40
ALLFTOOncogeneFTO bound IRF8 mRNA and leading mRNA degradation, and reduced level of IRF8 accelerates the advancement T-ALL.FTO/IRF8Targeted therapy for T-ALL patients75
ALLIGF2BP2OncogeneIGF2BP2 is necessary to T-ALL cell proliferation via binding to T-ALL oncogene NOTCH1.IGF2BP2/NOTCH1Targeted therapy for T-ALL patients76

AKT1, protein kinase b alpha; ALDH1A1, aldehyde dehydrogenase 1a1; ALKBH5, human AlkB homolog 5; ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; ASB2, ankyrin repeat and SOCS box containing 2; ATG16L1, autophagy related 16-like 1; BCL2, B-cell leukemia/lymphoma 2 protein; BM-MSCs, bone marrow mesenchymal stem cells; FOXO3, forkhead box O3; FTO, fat mass and obesity-associated; GPT2, generative pre-trained transformer 2; HIF1α, hypoxia-inducible factor 1-alpha; IGF2BP, insulin-like growth factor-2 mRNA-binding protein; IRF8, interferon regulatory factor 8; JAK1, Janus-activated kinase 1; KDM4C, lysine (K)-specific demethylase 4C; LDHB, lactate dehydrogenase-B; MCM4, minichromosome maintenance complex component 4; METTL3, methyltransferase-like 3; mTOR, mammalian target of rapamycin; MYB, myeloblastosis oncogene; MYC, myelocytomatosis oncogene; NOTCH1, neurogenic locus notch homolog protein 1; PFKP, phosphofructokinase platelet; PSMA3, proteasome subunit alpha type-3; PTEN, phosphatase and tensin homologue deleted on chromosome 10; RARA, retinoic acid receptor alpha gene; RCC2, regulator of chromosome condensation 2; TACC3, transforming acidic coiled-coil containing protein 3; USP1, ubiquitin-specific protease 1; WTAP, Wilms’ tumor 1-associated protein; WWTR1, WW domain-containing transcription regulator 1; YBX1, Y-box binding protein-1; YTHDC1, YTH domain-containing protein 1; YTHDF1, YTH N6-methyladenosine RNA binding protein 1.

Reversible m6A modifications involve demethylases, specifically FTO and ALKBH5, known as “eraser” complexes. These complexes have been extensively studied in leukemia, particularly in AML. Inhibiting ALKBH5, an m6A eraser, effectively hampers AML development and curtails leukemia stem cell self-renewal.57–62 The challenge of high relapse rates in AML, often attributed to chemotherapy resistance, was investigated using MeRIP-seq analysis on complete remission and relapse samples. The findings reveal dysregulated m6A methylation as a key factor in this process, with hypomethylated RNAs associated with altered cell differentiation. Notably, the m6A demethylase FTO exhibited heightened expression in relapse samples, contributing to increased drug resistance observed both in vivo and in vitro experiments. Knockdown of FTO resulted in enhanced cellular differentiation, particularly towards granulocytic and myeloid lineages, following treatment with cytarabine (Ara-C). The research identified FOXO3 as a downstream target of FTO, and decreased hypomethylation of FOXO3 mRNA resulted in reduced expression, hindering cell differentiation. The FTO-m6A-FOXO3 axis emerged as a central regulatory pathway influencing chemotherapy resistance in AML, emphasizing FTO as a promising therapeutic target.63 A separate investigation delved into the chromosomal abnormality t(8;21)(q22;q22) in AML, leading to the formation of the AML1-ETO fusion protein. Despite the favorable prognosis associated with t(8;21) AML, 30–50% of patients experience relapse and drug resistance. The role of m6A in AML development and its connection with AML1-ETO and m6A-related enzymes remains unclear. The research aimed to investigate the interplay between FTO and AML1-ETO, an enzyme responsible for m6A demethylation. In t(8;21) AML, FTO exhibits heightened expression, particularly among individuals with primary refractory disease. An affirmative regulatory loop has been identified between AML1-ETO and FTO. AML1-ETO enhances the expression of FTO by PU.1-mediated suppression of FTO transcription. Concurrently, FTO augments AML1-ETO expression while impeding YTHDF2-mediated degradation of AML1-ETO mRNA. Suppressing FTO activity inhibited cellular growth, enhanced cellular differentiation, and rendered t(8;21) AML cells sensitive to Ara-C. FTO operates through the regulation of its mRNA targets, particularly insulin-like growth factor binding protein 2 (IGFBP2), via an m6A-mediated mechanism. Targeting the AML1-ETO/FTO/IGFBP2 circuitry offers therapeutic potential for addressing resistance to Ara-C in patients with t(8;21) AML.64 Another study investigated the effects of exosomes isolated from mesenchymal stem cells in the bone marrow (BM-MSCs) containing FTO on AML. Previous research associated AML progression and chemotherapy resistance with exosomes derived from BM-MSCs, but the specific functions and molecular mechanisms remained unclear. The study aimed to explore the impact of FTO-carrying exosomes derived from BM-MSCs on the characteristics of AML cells. Findings indicated that exosomes originating from BM-MSCs and containing FTO enhanced cancer aggressiveness, stem cell properties, and resistance to the chemotherapy drug Ara-C in AML cells. This study identified that FTO-exosome-mediated demethylation of m6A modifications occurred in an lncRNA known as Glycolysis-associated lncRNA of colorectal cancer (GLCC1), leading to increased stability and expression. Conversely, GLCC1 functions as a driver oncogene, promoting cellular expansion and bolstering resistance to Ara-C in AML cells. Additional investigations revealed that demethylated GLCC1 served as a scaffold, facilitating the assembly of the IGF2BP1-c-Myc complex and activating subsequent c-Myc-associated signaling pathways that promote tumor growth. Silencing experiments validated that the enhancing effects of FTO-exosomes derived from BM-MSCs on cancer aggressiveness and drug resistance in AML cells depended on the presence of GLCC1 and c-Myc. In conclusion, the study provided insights into the molecular mechanisms of AML aggressiveness and chemoresistance enhanced by FTO-exosomes derived from BM-MSCs, highlighting the potential of targeting the GLCC1-IGF2BP1-c-Myc axis for AML diagnosis and therapy in clinical settings.65 In a study addressing chemotherapy challenges in AML patients, researchers investigated FTO’s role and the influence of the inhibitor Rhein on multidrug-resistant AML. They employed the Cell Counting Kit-8 reagent to evaluate Rhein’s impact on cell growth, migration, and apoptosis in AML cells, including those resistant to multiple drugs. Results revealed FTO overexpression in multidrug-resistant AML. Rhein demonstrated significant dose- and time-dependent inhibitory effects on proliferation and migration, induced apoptosis, and inhibited the AKT/mTOR pathways, even in resistant cells. Combining low doses of Rhein with azacitidine sensitized certain AML cells to chemotherapy. Overall, Rhein appears promising for treating multidrug-resistant AML by suppressing growth, inducing apoptosis, and enhancing chemotherapy sensitivity, offering a potential therapeutic option for such challenging cases.88

Numerous investigations have highlighted the pivotal role of m6A-associated genes in regulating AML initiation, progression, and drug resistance, while also demonstrating their significance in normal hematopoiesis. The involvement of m6A in interacting with “reader” proteins, including YTHDC1, HNRNPA2B1, and HNRNPC in the nucleus, and YTHDF1-3, IGF2BP1-3, and EIF3b in the cytoplasm, regulates processes such as splicing, translation, nuclear retention, and mRNA stability. Several of these readers, notably IGF2BP2, YTHDF2, and YTHDC1, exhibit oncogenic characteristics in AML. In continuation of this discussion, these findings are depicted in Table 1. Subsequently, we delved into elucidating these studies. For instance, YTHDF2 contributes to AML progression by enhancing miR-126 expression, a promoter of AML advancement and LSC self-renewal. Enhancing YTHDF2 inhibition promotes the expansion of HSCs, rendering it a promising candidate for AML treatment.66 In addition, YTHDF2 is responsible for reducing the lifespan of different m6A transcripts, contributing to the functionality of LSCs. This includes transcripts such as the tumor necrosis factor receptor TNFRSF2, whose increased expression in YTHDF2-deficient LSCs primes the cells for apoptosis. Interestingly, YTHDF2 does not play a critical role in normal HSC function; instead, its absence augments HSC activity. Consequently, YTHDF2 is recognized as an exceptional therapeutic target, where its inhibition selectively targets LSCs while fostering the proliferation of HSCs.67 The subtype of AML characterized by the t(8;21)(q22;q22.1) translocation, accounting for 4 to 8% of cases, represents a predominant category within AML and is characterized by frequent genetic abnormalities. YTHDF2 demonstrates overexpression in patients with t(8;21) AML, which correlates with an increased risk of relapse and inferior relapse-free survival.68YTHDF1, recognized as an oncogene in AML, affects AML through the translation of Cyclin E2, and Tegaserod can block its oncogenic activity.69IGF2BP2, highly expressed in AML, especially in LSCs, regulates glutamine metabolism as an m6A reader, making it a potential therapeutic target.70IGF2BP3, specifically overexpressed in AML, plays a critical role in cell survival through interaction with regulator of chromosome condensation 2 mRNA and maintenance of m6A-modified RNA expression.71YTHDC1, which enhances LSC self-renewal in AML, increases the expression of HOXB-AS3 spliceosome NR_033205.1 via m6A modification, offering new insights for AML treatment.72

Acute lymphoid leukemia (ALL)

ALL, a specific type of acute leukemia, entails widespread growth, extensive infiltration, and suppression of regular hematopoiesis.89 ALL is the most prevalent cancer in children under 15 years of age, amounting to 25% of such diagnoses.90 There are two primary classifications of ALL based on the immune cell phenotype: B-cell ALL, the predominant type, and T-cell ALL, which is generally known for its heightened aggressiveness.91 About 20–30% of ALL cases in adults and approximately 3–5% in children are characterized by the BCR-ABL fusion gene (BCR-ABL+ ALL). This subtype shows limited responsiveness to conventional chemotherapy, increases the risk of relapse, and is linked to an exceptionally poor outlook.92

Recent research uncovered the involvement of m6A modifications in the development of pediatric ALL harboring the ETV6/RUNX1 (E/R)-positive fusion gene, which is detected in approximately 25% of pediatric B-cell ALL cases. Sun et al.73 conducted a comparative analysis of METTL3 and METTL14 levels using RT-PCR (reverse transcription polymerase chain reaction) in a cohort of 37 pediatric patients with E/R-positive ALL, alongside six control subjects. They discovered a significant reduction in the expression levels of METTL3 and METTL14 in E/R-positive ALL compared to the control group, suggesting a potential contribution to both the onset and advancement of E/R-positive ALL. Another study found upregulation of m6A-modified methylases (METTL3, METTL14, and WTAP) and demethylases (ALKBH5 and FTO) in pediatric patients with E/R-positive ALL, based on an investigation into the expression levels of m6A catalytic enzyme genes in 33 such patients.74 Delving into various ALL subtypes is imperative to acquire a comprehensive understanding of the complete mechanism underlying m6A epigenetic modification in ALL.

Recent research indicated that ubiquitin-specific proteases (USPs) are implicated in T-cell ALL development and resistance to chemotherapy. Increased USP1 expression has been observed in glucocorticoid-resistant T-cell ALL patients and glucocorticoid-resistant cell line (CEM-C1) cells, correlating with a poor prognosis in T-cell ALL cases. Knockdown of USP1 heightened the sensitivity of CEM-C1 cells to dexamethasone, leading to decreased cell invasion, augmented apoptosis, and enhanced glucocorticoid receptor expression. USP1 modulates T-cell ALL chemoresistance through its interaction with and deubiquitination of Aurora B. ALKBH5, an m6A eraser, upregulated USP1 expression by reducing m6A levels and increasing mRNA stability in the USP1 transcript. The investigation confirmed that ALKBH5 downregulation decreased USP1 and Aurora B expression, thus promoting dexamethasone sensitivity, apoptosis, glucocorticoid receptor expression, and inhibiting cell invasion in CEM-C1 cells. Furthermore, experiments conducted in vivo using mice demonstrated that the intravenous injection of sh-USP1 notably suppressed tumor growth, resulting in prolonged survival. These findings offer valuable insights for clinical research on tumor treatment.93 Another study revealed that FTO, an m6A demethylase, plays a role in the progression of T-cell ALL by binding to m6A sites in the 3′ untranslated region of interferon regulatory factor 8 (IRF8) mRNA, leading to mRNA degradation through m6A modification. IRF8, a crucial transcription factor in determining hematological lineage commitment and capable of inhibiting T-cell ALL, is abnormally suppressed in T-cell ALL. Targeting the FTO-IRF8 axis in therapy, by inhibiting FTO’s demethylase activity, significantly reduces leukemic cell proliferation and extends the survival of mice with T-cell ALL by restoring IRF8 expression.75

In a related investigation, Feng et al.76 explored the function of the m6A reader IGF2BP2 in T-cell ALL. Their research provided evidence indicating that the increased expression of IGF2BP2 plays a critical role in promoting tumor cell proliferation in T-cell ALL, facilitated by its interaction with the NOTCH1 oncogene. A decrease in the expression level of IGF2BP2 resulted in extended survival in a human T-cell ALL xenograft model. Moreover, the development of the IGF2BP2 inhibitor JX5 effectively suppressed NOTCH1 activation and the progression of T-cell ALL, suggesting potential therapeutic benefits for T-cell ALL treatment.

m6A modification in chronic leukemia

Chronic myeloid leukemia (CML)

CML arises from the abnormal proliferation of multipotent hematopoietic stem cells in the bone marrow. Presently, CML has an annual incidence ranging from 0.7 to 1.8 per 100,000 individuals, making it the third most prevalent leukemia subtype.94,95 CML is marked by a translocation event involving chromosomes 9 and 22, culminating in the creation of the oncogenic BCR-ABL1 fusion gene.96,97 The resulting activation of the ABL1 protein tyrosine kinase induces modifications in various signaling pathways that regulate gene expression. Consequently, ABL1 tyrosine kinase inhibitors (TKIs) are extensively utilized for the clinical management and treatment of CML. Nonetheless, around 20% of CML patients develop resistance to TKIs.98

Recent reports suggest that METTL3, an RNA m6A modifier, plays a regulatory role in CML development (Table 2).98–104 Ianniello et al.98 discovered elevated expression of the m6A methyltransferase complex, composed of METTL3 and METTL14, in CML patients. This complex is crucial for sustaining the growth of both primary CML cells and CML cell lines, whether they are responsive or resistant to TKIs such as imatinib. The study revealed METTL3’s direct regulation of the oncogenic pescadillo ribosomal biogenesis factor 1 (PES1) protein, affecting genes linked to various tumors. METTL3 is crucial for activating genes involved in ribosome biogenesis and translation, and its depletion significantly hampers translation efficiency. Conversely, a deficiency in METTL3 severely impairs the efficiency of mRNA translation for genes related to metabolism in organisms. Utilizing inhibitors targeting the METTL3/METTL14 complex could serve as an effective therapeutic approach for eliminating TKI-resistant CML cells. Consequently, these findings suggest that METTL3 functions as a new oncogene in the progression of CML and could serve as a promising therapeutic focus for TKI-resistant CML. Another study revealed that METTL3 influences lncRNA nuclear-enriched transcript 1 (NEAT1) expression by regulating the miR-766-5p/CDKN1A axis. The elevated expression of NEAT1 reduced cell viability and triggered apoptosis in CML cells. The absence of METTL3 led to NEAT1 downregulation in both CML cell lines and peripheral blood mononuclear cells (PBMCs) of CML patients. Moreover, the direct binding of miR-766-5p with NEAT1 resulted in its upregulation in CML PBMCs, consequently counteracting the regulatory effects of NEAT1 on the survival and programmed cell death of CML cells. The results also revealed that CDKN1A, the gene targeted by miR-766-5p, exhibited downregulation in CML PBMCs, and suppressing it reversed the effects of NEAT1. This mechanism enables METTL3 to impact the advancement of CML and undertake a role conducive to oncogenesis.99 Additionally, Lai et al.100 found that METTL3 dysregulation could lead to chemotherapy resistance and proliferation of CML cells. The findings reveal an oncogenic role for LINC00470, positively regulating METTL3, which in turn inhibits PTEN mRNA expression. Furthermore, dysregulation of the LINC00470/METTL3 signaling pathway decreased the stability of PTEN and activated AKT, thereby promoting chemoresistance and suppressing autophagy in CML.

Table 2

m6A modification in chronic leukemia (CML & CLL)

Cancer typem6A modifiersRole in cancerBiological functionsMechanismsPotential clinical applicationRef
CMLMETTL3OncogeneMETTL3 regulates the PES1 level and ribosome biogenesis and translation-related genes, thereby leading to the proliferation of CML cellsMETTL3/PES1 protein pathwayPromising therapeutic target for TKI-resistant CML98
CMLMETTL3–The deficiency of METTL3 causes NEAT1 downregulation in CML which abrogates the effects of NEAT1 on cell viability and apoptosis of the CML cellsMETTL3/NEAT1/miR-766-5p/CDKN1A pathwayPotential diagnostic indicator or therapeutical target for CML99
CMLMETTL3OncogeneDysregulation of METTL3-induced chemoresistance and suppressed autophagy in CML cellsLINC00470/METTL3/PTEN mRNA pathway–100
CMLKIAA1429/YTHDF1OncogeneKIAA1429 regulated the total level of RNA m6A modification, promoted proliferation and migration, and imatinib resistance in the CML cellsKIAA1429/m6A/YTHDF1/RAB27B mRNANew anti-cancer agents and potential treatment for the imatinib-resistant CML cells101
CLLMETTL3OncogeneMETTL3 can regulate the levels of splicing factors through the translational control of m6A-modified mRNA, contribute to abnormalities in RNA splicing, and lead to disease progression in CLLNot availableA promising treatment target for aggressive CLL102
CLLHNRNPC, YTHDC1 and RBMXOncogeneRBMX and YTHDC1 affect the biogenesis and modulation of circTET2/circTET2 interacting with HNRNPC contribute to lipid metabolism and CLL progressionCP028/RBMX and YTHDC1/circTET2 circTET2/HNRNPC/FAO and mTORC1pathwaysPrognostic indicator and targeting treatment of CLL103
CLLFTOOncogeneFTO displays a regulatory role in tumorigenesis and progression of CLL and is linked to a poor prognosis in CLL patients.Not availableTargeted treatment in progressed CLL104

CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; FAO, fatty acid oxidation; FTO, fat mass and obesity-associated; HNRNPC, heterogeneous nuclear ribonucleoprotein C; METTL3, methyltransferase-like 3; mTOR, mammalian target of rapamycin; NEAT1, nuclear enriched abundant transcript 1; PES1, pescadillo ribosomal biogenesis factor 1; PTEN, phosphatase and tensin homologue deleted on chromosome 10; YTHDC1, YTH domain-containing protein 1; YTHDF1, YTH N6-methyladenosine RNA binding protein 1.

Other m6A modifiers also participate in CML progression. An inquiry has shown that KIAA1429, an m6A regulator, is significantly upregulated in patients in the blast phase of CML. This m6A regulator controls the overall extent of RNA m6A modification and amplifies adverse biological traits in CML cells, including migration, growth, and resilience to imatinib. Elevated levels of KIAA1429 during the accelerated phase of CML enhance the stability of RAB27B mRNA through the m6A/YTHDF1 axis, resulting in upregulated RAB27B expression and further advancement of CML. Rucaparib, a novel anti-cancer medication, suppresses KIAA1429 expression, thereby decreasing CML cell proliferation and facilitating apoptosis. Indeed, inhibiting KIAA1429 destabilizes RAB27B, suppressing CML proliferation and drug resistance, and enhancing sensitivity to imatinib.101 LSCs in CML, which are often insensitive to TKIs, contribute to disease relapse.105 A study revealed that RNA-binding proteins (RBPs) YBX1 regulates the survival of CML LSCs via modulating m6A-mediated YWHAZ stability.106 RBPs exert substantial regulatory influence on transcripts by regulating diverse processes such as RNA synthesis, alternative splicing, post-transcriptional adjustments, translation, and transport.107YBX1 expression rises in CML cells and is essential for LSC survival. YBX1 collaborates with RNA m6A reader IGF2BPs to augment the durability of the YWHAZ transcript in an m6A-associated manner. Therefore, targeting YBX1 can provide a new potential method for CML treatment.106

Chronic lymphocytic leukemia (CLL)

CLL is a common hematological disorder worldwide, with a global incidence of 42 cases per 100,000, particularly affecting individuals over 80 years old at a rate of 30/100,000/year.108 m6A modifications play crucial roles in the progression and viability of CLL patients, highlighting the potential for targeted interventions focusing on m6A modifications as a new treatment approach for advanced CLL.109,110 RNA splicing defects are pervasive across the CLL transcriptome, underscoring the crucial involvement of RNA splicing dysregulation in the pathogenesis of the disease. Integrative transcriptomic and proteomic examinations have revealed an elevation in post-transcriptional RNA splicing proteins within CLL cells, with a heightened prevalence of splicing complexes identified as a standalone predictor of unfavorable prognosis. Dysregulation of RNA splicing may arise from mutations in splicing factors or irregular expression of upstream regulators such as METTL3, an m6A writer (Table 2). METTL3 abundance is closely associated with increased splicing factor expression, as it controls the translation of mRNAs encoding splicing factors through m6A methylation-triggered ribosome pausing and recycling. This process results in dysregulated splicing, contributing to disease progression. Hence, METTL3 emerges as a potential therapeutic target in aggressive CLL.102 A distinct study explored the prognostic relevance of m6A modifications in CLL patients, particularly through the regulation of circRNAs, which play a crucial role in cancer metabolism. Wu and colleagues conducted an in-depth analysis of transcriptional sequencing data from 53 CLL patients to establish a prognostic signature based on m6A-modified circRNAs. Their research underscores the importance of m6A-modified circTET2 as a prognostic marker for CLL patients. BMX and YTHDC1, identified as m6A regulators, function as RBPs and are modulated by CP028. This study reveals that the formation and control of circTET2, which is elevated in CLL, are influenced by the RBPs RBMX and YTHDC1. Furthermore, circTET2, interacting with HNRNPC, plays a role in modulating fatty acid oxidation and the mTORC1 signaling axis, thus fulfilling energy requirements and promoting the growth of CLL cells. The concurrent inhibition of fatty acid oxidation and mTOR demonstrated increased efficacy, suggesting novel avenues for therapeutic intervention in CLL treatment.103 Accumulating evidence suggests that FTO plays a critical role in cancer development. FB23-2, a newly developed inhibitor, specifically targets the demethylase activity of FTO m6A and has exhibited notable efficacy in the context of AML. Zhang et al.104 explored the impact of FTO and FB23-2 on CLL tumor development and progression. The study revealed the carcinogenic role of FTO in CLL progression and elucidated how the FTO inhibitor FB23-2 regulates CLL cells. Increased FTO expression correlates with an unfavorable prognosis among CLL patients. FB23-2 exhibited notable therapeutic promise by efficiently inhibiting cellular viability and inducing cell cycle stasis via methylation of m6A. The study provides a foundation for evaluating FTO-targeted interventions and introduces an innovative treatment strategy for advanced CLL.

Conclusions

The intricate world of epitranscriptomics, particularly the impact of m6A modification, has unveiled a new frontier in understanding and combating hematological malignancies. The regulatory network involving m6A modifiers, such as writers, erasers, and readers, is crucial in shaping gene expression, thereby influencing critical cellular functions in both normal hematopoiesis and the pathogenesis of leukemia. Hematological malignancies present significant challenges in healthcare, necessitating constant research and innovative therapeutic strategies. Exploring m6A modifications in these cancers has provided crucial insights into the dysregulation of gene expression, offering potential avenues for targeted interventions. The dynamic landscape of m6A modifications in normal hematopoiesis highlights their importance in maintaining the delicate balance of blood cell development. As we delve deeper into the molecular mechanisms underlying AML, ALL, CML, and CLL, it becomes evident that m6A modifications are key players in disease progression. The identification of specific writers, erasers, and readers associated with each leukemia subtype opens doors to novel therapeutic targets and personalized treatment approaches. The role of genes in the detection and management of cancer cannot be overstated. The dysregulation of m6A modifiers underscores the potential of targeted therapies in mitigating leukemia progression. The m6A RNA methylation landscape provides not only diagnostic and prognostic markers but also novel therapeutic avenues for overcoming treatment challenges and improving patient outcomes. Furthermore, the emerging field of epigenetic approaches, particularly focusing on m6A modifications, holds great promise. Targeting specific m6A regulators, utilizing advanced technologies to modulate RNA methylation patterns, and exploring epigenetic therapies present exciting prospects for the future of leukemia treatment. In conclusion, the importance of hematological malignancies cannot be underestimated, and understanding the intricate roles of genes and epigenetic modifications, especially m6A RNA methylation, is crucial for advancing cancer research and improving patient care. The ongoing exploration of these molecular landscapes provides hope for more effective and personalized therapeutic interventions in the challenging realm of hematological cancers.

Declarations

Acknowledgement

None.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sector.

Conflict of interest

The authors have no conflict of interest related to this publication.

Authors’ contributions

Material preparation, data collection and analysis (ZM, PM, ZKK, SA), writing the first draft of the manuscript (ZM, PM). All authors contributed to the conception and design of the study. They commented on previous versions of the manuscript, read, and approved the final manuscript.

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