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N6-Methyladenosine (m6A) Methylation Modifications in Hematological Malignancies: History
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Subjects: Hematology
Contributor: yan zhao

Epigenetics is identified as the study of heritable modifications in gene expression and regulation that do not involve DNA sequence alterations, such as DNA methylation, histone modifications, etc. Importantly, N6-methyladenosine (m6A) methylation modification is one of the most common epigenetic modifications of eukaryotic messenger RNA (mRNA), which plays a key role in various cellular processes. It can not only mediate various RNA metabolic processes such as RNA splicing, translation, and decay under the catalytic regulation of related enzymes but can also affect the normal development of bone marrow hematopoiesis by regulating the self-renewal, proliferation, and differentiation of pluripotent stem cells in the hematopoietic microenvironment of bone marrow. In recent years, numerous studies have demonstrated that m6A methylation modifications play an important role in the development and progression of hematologic malignancies (e.g., leukemia, lymphoma, myelodysplastic syndromes [MDS], multiple myeloma [MM], etc.). Targeting the inhibition of m6A-associated factors can contribute to increased susceptibility of patients with hematologic malignancies to therapeutic agents.

  • epigenetics
  • N6-methyladenosine
  • normal hematopoiesis
  • leukemia
  • multiple myeloma
  • myelodysplastic syndrome

1. Introduction

Hematologic malignancies are a wide group of malignant clonal disorders of hematopoietic cells. Importantly, they typically manifest as uncontrolled proliferation and differentiation disorders of the hematopoietic cells, with high heterogeneity and poor prognosis, and so far, there is the lack of an effective cure. Currently, emerging evidence has revealed that the incidence of hematological malignancies ranks 6th in the total incidence of cancer in the world and 1st in the mortality rate of malignant tumors in adolescents [1]. Hematologic tumors are the second most common cause of cancer death in the United States. The occurrence of hematologic tumors is a complex multi-step process, and the malignancies mainly include lymphoma, leukemia, and myeloma, among other hematologic malignancies. In recent decades, studies [2][3] have shown that the pathogenesis of such diseases is associated with a variety of factors, including genomic abnormalities, epigenetic alterations, abnormal regulation of the bone marrow hematopoietic microenvironment, and disorders of the immune system.
In addition to the increasing number of patients suffering from this malignancy each year [1], inappropriate treatment modalities also lead to an annual increase in the mortality rate of this disease, which has inspired doctors to look for better treatment strategies. Notably, the progress of gene editing technologies and their application in the field of hematological tumors over the past decades have led to significant developments in the diagnosis and treatment of these malignancies [2]. Meanwhile, these findings shed light on the different mechanisms involved in the pathogenesis of hematologic malignancies [3]. Nevertheless, while most previous studies have focused on the study of genetic mechanisms of hematologic malignancies [4], recently, more attention has been paid to the field of epigenetics, which involves many closely related mechanisms regulating changes in gene expression levels without involving alterations in the DNA sequence [5].
In recent decades, epigenetics has been identified as a novel concept that corresponds to genetics and encompasses many types of well-documented epigenetic modifications. In plain words, epigenetic modification is a form of gene expression regulation that affects gene transcription and translation without changes in the nucleotide sequence and can regulate and thus affect gene expression at the level of DNA and chromatin structural modifications, RNA stability, and transcriptional activity, including DNA methylation modifications, histone covalent modifications, chromatin remodeling, non-coding RNA regulation, RNA modifications, etc. [6][7][8]. Further, epitranscriptomics is one of the newly emerging hot fields, which mainly focuses on the effects of chemical modifications carried by RNAs and their correlated regulators on gene expression. To date, it has been reported that more than one hundred chemical modifications (e.g., m6A) have been identified on RNAs, which perform extremely significant biological functions in living organisms via their involvement in mediating epigenetic regulation. More importantly, in recent years, epigenetic modifications have played a highly important role in the development and progression of hematologic malignancies (Figure 1).
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Figure 1. Potential epigenetic regulatory mechanisms in hematologic malignancies. Epigenetic modifications are heritable alterations that can generate changes in gene activity independent of changes in gene nucleotide sequences, including DNA methylation, histone modifications, chromatin remodeling, non-coding RNA, and RNA and RNA modifications, etc., which primarily mediate changes in gene transcription as well as translation activity. Numerous studies have confirmed that epigenetic modifications (e.g., DNA methylation and histone modifications) play an essential role in the development and progression of hematologic malignancies and are considered to be a vital target for the treatment of different types of leukemias and other hematologic malignancies.
At present, epitranscriptomics, represented by N6-methyladenosine (m6A) modifications, has become a hot topic of research due to the current study of second-generation sequencing, i.e., targeting their epigenetic alterations at the transcriptome level [9][10][11][12]. In essence, m6A methylation modifications can mediate the post-transcriptional regulation of gene expression without altering base sequences. In addition, RNA m6A modification is reversible and dynamically modulated by m6A modifiers (e.g., writers, erasers, and readers), which have currently been proven to play an important role in regulating mRNA decay, stability, variable splicing, translation efficiency, and localization [11][13][14]. Moreover, m6A sites are also present in long non-coding RNAs as well as non-coding RNAs such as microRNAs.
With the rapid development of high-throughput m6A sequencing technology in recent years, accumulated evidence has supported that m6A and its related factors are involved in the hematopoietic development of bone marrow by regulating the self-renewal, proliferation and differentiation of pluripotent stem cells in the bone marrow hematopoietic microenvironment. Identically, emerging studies [4][7][15][16] have indicated that abnormal m6A modification is closely associated with the development and progression of hematologic malignancies. In this paper, we systematically review the progress of research on the biological characteristics of m6A methylation modifications, their effects on normal hematopoietic regulatory functions, and their role in hematologic malignancies. It is expected to provide a scientific basis for the development of novel molecularly targeted therapies based on the aberrant m6A modifications in related hematologic tumors.

2. Biological Features of m6A Methylation Modifications

2.1. Overview of m6A Methylation

RNA epigenetic modifications are an important part of RNA regulation [17]. Currently, more than 150 RNA modifications have been identified in eukaryotes, mainly occurring on mRNA, tRNA, rRNA, and other non-coding RNAs, which are regulated at the post-transcriptional level [18]. Of note, the m6A is a methylation modification located on the sixth nitrogen atom of RNA adenine, which is the most common type of modification in higher eukaryotic mRNAs [19][20], and the number of m6A modified adenines accounts for 0.2 to 0.5% of the total number of adenines [21]. Moreover, m6A modification is widely found not only in mammals but also in yeast, plants, protozoa, and various viruses [22][23]. With the rapid development of high-throughput sequencing technology, it has been recently found that m6A is sequentially distributed in the protein-coding sequence (CDS), near the stop codon and in the 3’ untranslated region (3’UTR) [24][25][26], i.e., mainly localized in the highly conserved sequence of mRNA RRACH motif (R = G/A; H = U/A/C) [27][28][29]. In addition, m6A methylation modifications are widely distributed in mRNA and non-coding RNA (ncRNA) and play important roles in the metabolism of many RNAs, including mRNA splicing, processing and maturation of microRNA (miRNA), and long non-coding RNA (lncRNA)-mediated transcriptional repression [30][31][32].
Precisely, m6A was first discovered in the mRNA of hepatocellular carcinoma cells in 1974 [20][33] and has since been detected in a variety of eukaryotic organisms such as mice and yeast whose biological functions involve cell differentiation, mitosis, immune homeostasis, and other aspects. As a dynamic and reversible epistatic modification, m6A possesses many recognition proteins, which can be classified into three major categories: “Writers”, “Erasers”, and “Readers”, according to their functions [11] (Figure 2). Importantly, the enzymatic reaction process is divided into three modification states in sequence according to the classification: (1) mRNA is methylated by the writer (m6A methyltransferase); (2) the process can be reversed by the eraser (m6A demethylase); and (3) the methylated mRNA is recognized by the reader (m6A binding protein) [32]. To sum up, the specific mechanism of m6A is illustrated as follows.
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Figure 2. The complete process of m6A methylation modification. The m6A methylation modification is a dynamic and reversible enzymatic process and is strictly modulated by writers, erasers, and readers. (A) First, mRNA methylation is catalyzed by writers (e.g., m6A methyltransferases METTL3, METTL14, WTAP, RBM15, VIRMA, and ZC3H13, etc.); (B) Second, the process can be reversed by erasers (e.g., m6A demethylases FTO and ALKBH5); (C) Finally, the methylated mRNA will be recognized by readers (e.g., m6A binding proteins YTHDF1/2/3, YTHDC1/2, HNRNPs, IGF2BP, eIF3, etc.), thereby fulfilling the corresponding physiological roles. Specifically: ① mRNA splicing: YTHDC1, HNRNPA2/B1, HNRNPC/G, etc.; ② miRNA processing: HNRNPA2/B1; ③ mRNA translocation: YTHDC1; ④ mRNA structure: HNPNPC; ⑤ mRNA storage: IGF2BPs; ⑥ mRNA stability: IGF2BPs; ⑦ mRNA translation: YTHDF1/2/3, YTHDC2, IGF2BPs, eIF3, etc.; ⑧ mRNA decay: YTHDF2/3, YTHDC2.

2.2. m6A-Related Enzymes

2.2.1. m6A Methyltransferase (Writers)

The m6A methyltransferase is also known as the writer [34]. The core components of the m6A methyltransferase complex, which performs m6A methylation, include three main species: METTL3 (methyltransferase-like 3), METTL14 (methyltransferase-like 14), and WTAP (Wilms’ tumor 1-associating protein) [35][36][37]. In fact, the m6A methyltransferase complex adds m6A methylation to the target mRNA through the methyl group on S-adenosylmethionine (SAM) transferase [38][39]. Among them, METTL3, with its N-terminal structural domain, methyltransferase structural domain, and two tandem zinc finger structural domains, is the main catalytic structure; on the other hand, METTL14 has a strong interaction with METTL3, but its methyl donor site is degraded and does not have catalytic activity, so it only plays a catalytic auxiliary role for METTL3 and maintains METTL3 activity [30][40]. METTL3–METTL14 heterodimer formation can induce m6A deposition on mammalian nuclear RNA [41][42]. Moreover, WTAP is not catalytically active, but it can help localize the complex to the nucleus and promote affinity between the complex and mRNA [43][44][45].
Indeed, METTL3 can catalyze the methylation modification of most mRNAs in vivo, and its homologue, METTL16 (methyltransferase-like protein 16), regulates the m6A modification of U6snRNA and a small fraction of mRNAs [46][47]. In addition, there are METTL5 (methyltransferase-like 5), ZCCHC4 (zinc finger CCHC-type containing 4), etc., which also have some catalytic functions for m6A on rRNAs [48]. In the methyltransferase complex, some new components including VIRMA (vir-Like m6A methyltransferase associated) [49][50][51], RBM15/15B(RNA binding motif protein 15/15B) [52], ZC3H13 (zinc finger CCCH-type containing 13) [53][54], etc. can interact with WTAP directly or indirectly as regulatory subunits, which together with WTAP form the MACOM complex and direct the localization of the whole complex in the cell [55][56]. Similarly, the activity of the methyltransferase complex is also susceptible to the influence of miRNAs [57].
Currently, it is generally known that m6A is co-transcriptionally modified on transcripts, and then METTL3 is recruited to chromatin in a transcription-dependent manner, mediating the methylation of nascent transcripts, and that the degree of methylation is strongly correlated with the activity of RNA polymerase II [58]. However, how the methyltransferase complex recognizes the substrate RNA and how the activity of the complex is regulated remain to be further investigated.

2.2.2. m6A Demethylases (Erasers)

The m6A demethylases are called erasers, and their role is to catalyze the removal of methyl from m6A that has been methylated. Mechanistically, m6A methyltransferases and demethylases affect post-transcriptional gene expression levels by regulating dynamic changes in m6A methylation modifications of mRNA sequences. In fact, the two types of m6A demethylases identified so far are FTO (fat mass and obesity-associated gene) [59] and ALKBH5 (alkB homolog 5) [60]. It has been reported that FTO is an obesity-associated protein with the role of catalyzing m6A demethylation [59][61]. FTO belongs to the α ketoglutaric acid (α-KG) and divalent iron ion Fe(II) dependent ALKB dioxygenase family, which is localized in both the nucleus and cytoplasm of cells [61]. It possesses two structural domains: the N-terminal domain, which is conserved with the dioxygenase family sequence, and the C-terminal domain, which mainly plays a scaffolding role. The mechanism by which FTO affects the demethylation of m6A is that m6A is first oxidized to hm6A (N6-hydroxymethyladenosine) and f6A (N6-formyladenosine), then formaldehyde and formic acid are removed to complete the demethylation. Ultimately, adenine is produced [40][62].
However, the substrate of FTO is not only m6A but also N6,2’-O-dimethyladenine (m6Am) and m1A on tRNA are its catalytic substrates [11]. For example, in 2019, Guifang Jia’s group obtained the crystal structures of the human FTO nucleic acid complexes and resolved the interaction mechanism of FTO with each substrate [63]. It was found that although the FTO active pocket can recognize molecules of multiple RNA modification substrates, it prefers to bind N6-methyladenine bases and has the same demethylation activity for internal m6A and m6Am with the same RNA sequence (N6-methyladenine bases), indicating that the demethylation activity of FTO is mainly dependent on the recognition of residues and bases in its catalytic pocket rather than on the ribose ring and that different RNA sequences and tertiary structures also affect the catalytic function of FTO. Thus, these findings provide an understanding of the catalytic mechanism of how FTO demethylates a variety of substrates and provide potential research directions for future selective chemistries for cancer therapy.
In recent studies, ALKBH5 was identified to be localized in the nucleus, and either silencing or overexpression of ALKBH5 could alter m6A levels [60]. More importantly, ALKBH5, similar to FTO, is also a member of the divalent iron ion, α-KG-dependent ALKB dioxygenase family. However, unlike FTO, the demethylation regarding the m6A modification site of target genes mediated by ALKBH5 does not require a multi-step reaction but is performed directly. At present, it has been indicated that ALKBH5 may regulate the out-of-nucleus transport of mRNAs [11], which is ultimately involved in the development of multiple diseases [64]. Therefore, as an m6A demethylase, it has been conclusively demonstrated that the knockdown of ALKBH5 in mouse models does not affect health status other than causing impaired spermatogenesis in mice, which makes ALKBH5 a potential therapeutic target in the future [65][66]. Collectively, the discovery of methyltransferases and demethylases confirms that m6A modification is dynamically reversible and that both work together to maintain a dynamic balance of cellular m6A methylation and demethylation.

3. m6A Methylation Modification and Normal Hematopoietic Regulation

To date, further studies on the function of m6A-related enzymes confirmed that abnormal activity of these genes led to abnormal expression of thousands of genes, firmly suggesting an important role of m6A in RNA metabolism. Specifically, m6A may affect lipid metabolism [67], sperm development [68], tumorigenesis, stem cell-directed differentiation [69], cellular reprogramming [70], biological clock rhythms, cell division, memory, and neurodevelopment [71], as well as several other life processes. Therefore, given the critical role of m6A in the regulation of epigenetic events, these classes of enzymes have been identified to be involved in a variety of cellular life activities, particularly in the normal regulation of hematopoiesis in the hematological system (Figure 3).
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Figure 3. m6A methylation modifications and normal hematopoietic regulation. This image depicts the role of RNA m6A methylation in normal human hematopoiesis. (a) The development and differentiation process with respect to human normal hematopoietic stem/progenitor cells (HSPCs) is presented here, i.e., from HSPCs to terminally differentiated erythroid, lymphoid, and myeloid cells; (b) It has revealed that m6A modification modulates the normal hematopoietic system. ① METTL3-mediated m6A modifications regulate HSPC fate specification via suppressing Notch signaling during early definitive hematopoiesis. ② During the expansion of HSPC in the fetal liver, METTL3 deletion promotes the formation of dsRNA, activates the OAS RNase L and PKR-eIF2a pathways, and upregulates MDA5/RIG-I, resulting in hematopoietic failure. ③ METTL14 is highly expressed during the development of normal CD34 HSPCs cells, and silencing METTL14 facilitates terminal myeloid differentiation of HSPCs cells. ④ In R-2HG-sensitive leukemic cells but not in normal CD34 HSPCs, overexpression of FTO reverses the effect of R-2HG-induced glycolysis inhibition, leading to leukemogenesis in vivo. ⑤ Deficiency of YTHDF2 causes the failure of hematopoietic stem cells during serial transplantation and prolonged activation of pro-inflammatory pathways, ultimately contributing to progressive bone marrow bias. ⑥ YTHDC1 deletion impedes the proliferation and survival of LSCs in vivo, supporting the oncogenic role of YTHDC1 in leukemias (e.g., AML). Abbreviations: HSPCs hematopoietic stem/progenitor cells; MPP multipotent progenitors; LMPP lymphoid-primed multipotential progenitors; CMP common myeloid progenitor; CLP common lymphoid progenitor; GMPs granulocyte/monocyte progenitor; MEPs megakaryocytes/erythroid progenitor; Gn granulocyte; DC dendritic cell; M monocyte; E erythrocyte; NK natural killer cell; EHT endothelial-to-hematopoietic transition; LSCs leukemia stem cells; HE hemogenic endothelial; R-2HG R-2-hydroxyglutarate.++

4. m6A Methylation Modifications and Hematological Malignancies

Hematologic malignancies, a heterogeneous group of malignancies, occur as a result of malignant transformation of HSPCs, which lose the ability to further differentiate and mature, and thus are blocked at different nodes [72]. They can be divided into two types: myeloid and lymphocytic. Furthermore, the specific disease classification consists of the following four major areas: various types of leukemia, multiple myeloma, malignant lymphoma, and myelodysplastic syndromes. Among them, multiple myeloma accounts for ~10% of the overall incidence in hematologic malignancies [73]. However, the incidence of MM has steadily increased in recent years.
Recent studies have shown that RNA m6A methylation is closely correlated with various malignant diseases and their related processes. Here, we concentrate only on RNA m6A methylation in human cancers related to the hematological system. At present, a large number of studies have confirmed the considerable place of aberrant RNA m6A expression in the development, progression, and recurrence of different types of hematologic malignancies (Table 1).
Table 1. The functional roles of RNA m6A methylation modification in various types of hematologic malignancies.
Cancer Type m6A Modifiers Patients/Cell Lines Role of m6A in Cancer Functions Mechanism References
ALL Writers/Erasers In ETV6/RUNX1-positive ALL patients oncogene High levels of m6A “writers” (METTL3, METTL14, WTAP) and m6A “erasers” (FTO and ALKBH5) mRNA expression prior to induction therapy resulted in a high disease burden in ALL patients Not available [74]
  METTL3/METTL14 In childhood ETV6/RUNX1-positive P-ALL oncogene The decreased levels of METTL3 and METTL14 indicate a possible role in the pathogenesis and progression of E/R-positive P-ALL. Not available [75]
  ALKBH5 In glucocorticoid (GC)-resistant T-ALL patients/CEM-C1 cells/mice oncogene Inhibition of ALKBH5-mediated m6A modification decreased USP1 expression, and downregulation of USP1 ameliorated GC resistance in T-ALL by suppressing Aurora B expression and elevating GR levels ALKBH5/USP1/Aurora B [76]
AML YTHDC1 In human AML cells/LSCs in vivo in mice oncogene YTHDC1 is overexpressed in AML, and it contributes to the proliferation and survival of human HSPCs/AML cells, as well as the self-renewal of leukemia stem cells (LSCs) in mice YTHDC1/ MCM4 [77]
  YTHDC1 In AML cells oncogene nYACs maintain mRNA stability, as well as AML cell survival and undifferentiated state; moreover, nYACs protect m6A-mRNA from degradation by PAXT complex and exosome-related RNAs YTHDC1-m6A condensates (nYACs) [78]
  YTHDF2 In leukemic cells in vitro and in mice/in AML patients oncogene Overexpressed in t (8; 21)-type AML patients; when YTHDF2 is knocked down, it inhibits tumor cell proliferation in vitro and in mice AML1/ETO-HIF1α loop/YTHDF2/TNFRSF1b [79]
  YTHDF2 In mouse and human AML oncogene YTHDF2 contributes to the initiation of AML disease as well as proliferation and maintains the overall functional integrity of LSCs YTHDF2/ TNFR2 [80]
  YBX1/IGF2BPs Primary human and mouse AML cells in vitro and in vivo oncogene Expression of YBX1 is markedly upregulated in myeloid leukemia cells, and YBX1 deficiency greatly induces apoptosis and promotes differentiation while reducing proliferation and impairing leukemic competence of primary human and mouse AML cells in vitro and in vivo YBX1/MYC/BCL2 (mRNA) [81]
  METTL3 In MOLM-13 cell lines/recipient mice in vivo oncogene METTL3 is highly expressed in AML cells as well as promotes AML cell proliferation and inhibits cell differentiation; m6A modification elevates the translation levels of c-MYC, BCL2, and PTEN gene mRNAs in AML cells METTL3/c-MYC/BCL2/PTEN (mRNA) [82]
  METTL3 In AML cells and immunodeficient mice oncogene In AML cells, METTL3 promotes tumor cell proliferation and inhibits cell differentiation; downregulation of METTL3 results in the inability of immunodeficient mice to develop leukemia. CEBPZ/ METTL3/ SP1 [83]
  METTL14 In normal HSPCs and AML cells oncogene METTL14 is overexpressed in AML cells and can block the differentiation of normal myeloid cells and promote malignant hematopoiesis via m6A modifications SPI1-METTL14-MYB/MYC [84]
  WTAP In AML patients/WTAP knockout AML cells oncogene WTAP promotes AML cell proliferation, tumorigenesis, and inhibits cell differentiation. In addition, WTAP causes chemoresistance in AML cells WTAP/MYC mRNA [85]
  WTAP In AML patients or in AML cells in vitro in vivo oncogene miR-550-1 leads to a further decrease in WWTR1 stability by downregulating the expression level of WTAP, which ultimately disrupts AML cell proliferation and tumorigenesis miR-550-1/WTAP/ WWTR1 [86]
  WTAP In different AML cell lines, e.g., K562 cell line oncogene Under the regulation of functional METTL3, the expression of WTAP is upregulated and promotes the proliferation of AML cells METTL3/WTAP [87]
  FTO In vitro, in mice, primary patient cells, and TKI-resistant cells oncogene SsD inhibits AML cell proliferation and promotes apoptosis and cell cycle arrest via targeting FTO/m6A signaling both in vitro and in vivo Not available [88]
  FTO In AMLs oncogene FTO enhances leukemia oncogene-mediated cell transformation and leukemogenesis and suppresses all-trans retinoic acid (ATRA)-induced AML cell differentiation and apoptosis FTO/ASB2, RARA [89]
  FTO In (R-2HG-sensitive) leukemia cells oncogene R-2HG abrogated FTO/m6A/YTHDF2-mediated post-transcriptional upregulation of PFKP and LDHB (two key glycolytic genes) expression, thereby attenuating aerobic glycolysis in leukemia FTO/m6A/PFKP/LDHB axis [90]
  FTO In human AML cell lines and AML patients oncogene FTO inhibitors, namely FB23 and FB23-2, inhibit proliferation and promote differentiation/apoptosis in human AML cells and primary cells Not available [91]
  ALKBH5 In human AML LSCs oncogene By regulating the chromatin state of the ALKBH5 locus, the expression of ALKBH5 can be elevated, thereby maintaining leukemogenesis in human AML KDM4C, MYB, Pol II /ALKBH5/AXL Signaling Axis [66]
  ALKBH5 In human AML/in LSCs/LICs oncogene ALKBH5 not only facilitates the proliferation of AML cells, but also contributes to the self-renewal of leukemic stem/initiating cells (LSCs/LICs) ALKBH5/TACC3 [65]
CML METTL3 In CML patients/CML cell lines oncogene Depletion of METTL3 strongly impairs the translation efficiency of mRNA and contributes to the proliferation of CML cells METTL3/PES1 protein [92]
  METTL3 PBMCs and CML cell lines oncogene Overexpression of NEAT1 inhibits cell viability and promotes apoptosis in CML cells METTL3/NEAT1/miR-766-5p/CDKN1A axis [93]
  METTL3 In a mouse model, and in KCL22 and K562 cells oncogene Dysregulation of METTL3 promotes chemoresistance and inhibits autophagy in CML cells LINC00470/METTL3/PTEN mRNA [94]
DLBCL m6A regulators In DLBCL patients oncogene In patients with DLBCL, high-risk m6A indicates worse survival when grouped according to prognostic characteristics Not available [95]
  METTL3 In DLBCL tissues and cell lines oncogene METTL3 promotes tumor cell proliferation METTL3/ PEDF [96]
  WTAP In xenograft DLBCL models oncogene piRNA-30473 facilitates the proliferation of DLBCL cells and induces cell cycle arrest via upregulating WTAP piRNA-30473/WTAP/HK2 m6A [97]
MM ALKBH5 in MM cells, xenograft models or patients oncogene ALKBH5 deficiency induces apoptosis and inhibits the growth of MM cells in vitro ALKBH5/ TRAF1/NF-κB and MAPK [98]
  FTO in CD138 cells from MM+ oncogene IDH2 promotes the growth of myeloma cells in vitro by targeting FTO to regulate the m6A RNA level of MM IDH2/FTO/WNT7B/Wnt [99]
  HNRNPA2B1 in MM patients and in MM cells oncogene Overexpression of HNRNPA2B1 promotes the proliferation of MM cells in vitro and in vivo HNRNPA2B1/ILF3 mRNA/AKT3 [100]
MDS YTHDC1 In MDS cells oncogene Causes abnormalities in hematopoietic function YTHDC1/SRSF3 or SRSF10 [101]

This entry is adapted from the peer-reviewed paper 10.3390/cancers14020332

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