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Physio-pathological effects of N6-methyladenosine and its therapeutic implications in leukemia

Abstract

N6-methyladenosine (m6A), the most prevalent epigenetic modification of RNA in mammals, has become a hot topic throughout recent years. m6A is involved with every links of the RNA fate, including RNA splicing, nuclear export, translation and stability. Due to the reversible and dynamic regulatory network composed of ‘writers’ (methylase), ‘erasers’ (demethylase) and ‘readers’ (m6A binding proteins), m6A has been deemed as an essential modulator in vast physiological and pathological processes. Previous studies have shown that aberrant expression and dysfunction of these regulators are implicated in diverse tumors, exemplified by hematological malignancies. However, we should hold a dialectic perspective towards the influence of m6A modification on leukemogenesis. Given that m6A itself is neither pro-oncogenic nor anti-oncogenic, whether the modifications promote hematological homeostasis or malignancies occurrence and progression is dependent on the specific targets it regulates. Ample evidence supports the role of m6A in maintaining normal hematopoiesis and leukemogenesis, thereby highlighting the therapeutic potential of intervention in m6A modification process for battling leukemia. In this review, we introduce the advances of m6A modification and summarize the biological functions of m6A in RNA metabolism. Then we discuss the significance of several well-studied m6A regulators in modulating normal and malignant hematopoiesis, with focus on the therapeutic potentials of targeting these regulators for battling hematopoietic malignancies.

Introduction

Hematopoietic homeostasis is a delicately orchestrated balance between the proliferation and differentiation of hematopoietic stem/progenitor cells (HSCs) [1]. Accumulated genetic and epigenetic abnormities will deflect HSCs’ trajectory and convert HSCs into leukemia stem cells (LSCs), leading to malignant expansion of poorly differentiated cells [2]. Among all those hematological malignancies, acute myeloid leukemia (AML) is the most well-learned one, characterized by high lethality, unfavorable prognosis, frequent relapse and chemotherapeutic resistance [3]. Numerous factors can drive the occurrence and development of AML, among which epigenetics has been underlined by increasing evidence. Generally speaking, epigenetics centers on heritable variations in gene expression or cell phenotype without changing the nucleotide sequence. It can be classified as transcriptional, posttranscriptional and posttranslational, depending on the levels of modifications. Mounting evidences showed an important determinant of epigenetic abnormalities in the initiation and progression of hematological malignances, emphasizing the potential of novel epigenetic therapies [4, 5]. Until now, therapeutics targeting DNA methyltransferase and histone deacetylase have achieved remarkable effects against AML [4]. In addition to the well-studied DNA methylation and histone modification, RNA modifications exert modulatory roles at the post-transcriptional level.

For the past few years, the implication of RNA modification in AML have refueled the scientific interest in developing new therapeutic strategies. Among over 170 kinds of RNA modifications [6], N6-methyladenosine (m6A), which refers to methylation at the N6 position of adenosine, is identified as the most prevalent and abundant one [7]. Owing to the development of high-throughput sequencing, several cutting-edge m6A identification method has emerged, such as m6A-seq and miCLIP-seq, which gradually shape the cellular m6A landscape [7,8,9]. m6A marks exist in approximately 1/3 of the mRNAs, while a majority of these hold only one m6A mark, only a minority harbor more than 20 [10]. With our perception of regulatory machinery improving, m6A methylation is verified to play a crucial role in RNA fate, including splicing, nuclear export, translation, stabilization, and phase separation. Notably, the m6A modifications are not exclusive for mRNA, but also found in many other RNAs, including transfer RNA (tRNA), ribosomal RNA (rRNA), and long noncoding RNA (lncRNA) etc. Continuous evidences indicate that m6A methylation is widely involved in fate of other RNAs, such as the expression and stabilization of lncRNAs [11, 12], processing of pri-miRNA and maturation of miRNA [13], metabolism of circRNA [14]. Regulating gene expression via methylation and demethylation, m6A participates in numerous biological and pathological processes, including multiple human malignancies, adipogenesis and type2 diabetes [15,16,17].

In this review, we summarize the established knowledge on m6A methylation in mRNA metabolism, then describe the mechanisms and biofunctions of several crucial m6A regulators in normal hematopoiesis and leukemogenesis, particularly focusing on their potential value as targets for clinical therapy.

Regulation of m6A RNA modification

Writers (methyltransferases)

The functions in cellular m6A deposition are achieved by a multicomponent methyltransferase complex (MTC), a heterodimer composed of METTL3 and METTL14 [18], as well as the regulatory subunits WTAP [19], RBM15 [20], VIRMA [21], and ZC3H13. METTL3, the first identified writer [22], is the catalytic subunit of MTC. It is composed of nuclear localization signal (NLS) domain, leading helix structure (LH) domain, CCH-type zinc finger domain (ZFD), and two methyltransferase domains (MTD). NLS and LH mediate the interaction between METTL3 and METTL4, MTD binds to the methyl donor SAM and ZFD is responsible for recognizing targets [23, 24]. The target sites of METTL3 are enriched in the motif RRACH (R = G or A, H = A, C, or U) in the 3' untranslated region (3' UTR), in the long internal exon, and near the stop codon in mRNA [7]. As for METTL14, its crucial role in facilitating RNA substrate binding has been widely accepted [23]. And it can be promoted by PRMT1 via methylating its C-terminus [25]. WTAP is responsible for the localization of METTL3/METTL14 into nuclear speckles and recruiting them to targets. Meanwhile, its function and homeostasis are under the regulation of the complex [19, 26]. RBM15, along with its paralog RBM15B, recruits MTC to specific sites of mRNA and lncRNA X-inactive specific transcript (XIST) [20, 27]. VIRMA, the largest constituent of methyltransferase indispensable for the entire methylation process [28], recruits METTL3/METTL14/WTAP to selectively deposit in the 3' UTR and near the stop codon [21, 29]. ZC3H13 plays a vital regulatory role by anchoring the complex in the nucleus, the loss of which will initiate export of nuclear WTAP followed by lack of METTL3/METTL14 [30, 31]. METTL16 has been recognized as a conserved U6 snRNA methyltransferase with a comparatively limited scope of targets with a conserved UACAGAGAA sequence, independent of MTC [32,33,34]. The N-terminal domain exerts the enzymatic activity, while the C-terminal is composed of two vertebrate-conserved regions (VCRs) [35, 36]. METTL16 was verified to bind to hairpin in the 3' UTR of MAT2A, participating in the homeostasis of SAM by regulating the stability of the SAM synthetase in a m6A-dependent manner [34]. Recently, METTL16 has been found to exert both methyltransferase activity-dependent and -independent functions, similar to METTL3 [37]. Moreover, some studies have revealed the mechanisms of m6A modifications on other RNAs. For instance, ZCCHC4 is found to modify 28 S ribosomal RNA [38, 39], and METTL5/TRMT112 complex is supposed to correlate with 18 S rRNA [40].

Erasers (demethylases)

Erasers are a group of regulators that remove m6A deposition, mainly including the Fe2 + and alpha-ketoglutarate (a-KG)-dependent AlkB family members FTO and ALKBH5 [41, 42]. In particular, the discovery of FTO indicates the m6A modification is a reversible process, representing a milestone in the research of m6A. Although FTO and ALKBH5 are homologues, it has been observed that they have different substrate affinity, due to their distinct active-site residues [43]. In contrast to ALKBH5, which exclusively demethylates m6A, the principal substrate of FTO remains controversial [44, 45]. Mauer et al. hold that FTO’s primary target was not m6A but N6,2'-O-dimethyladenosine (m6Am), since m6A start to be demethylated by FTO at a concentration twice of m6Am in vitro [44, 46]. But Zhang et al. has discovered FTO exhibits equivalent catalytic activity toward m6A and m6Am after displaying on the same RNA sequence [47]. In vivo, according to the study conducted by Wei et al., FTO regulate m6A in nucleus, but this affinity bias tends to be inconspicuous in cytoplasm, which is ascribed to the abundance of m6A in nuleus [45]. Furthermore, m6A in mammalian transfer RNA (tRNA) has been found as a novel substrate of ALKBH3, and demethylation can significantly enhance the translation efficiency in vitro [48].

Readers

Upon recognizing and binding to specific m6A sites, readers mediate the distinct functions in regulating RNA fate and gene expression [49]. YT521-B homologue (YTH) protein family, as the first group of readers, is composed of YTHDF1/2/3 and YTHDC1/2. Among them, only YTHDC1 localizes to the nucleus while the rest in cytoplasm [50, 51]. With YTH domain directly binding to m6A marks, they are extensively involved in RNA metabolism [52,53,54]. DF proteins are found to bind to CNOT1 and mediate the deadenylation of mRNA [55]. And it was revealed that YTHDC2 can function as helicase independent of m6A, enhanced by its interaction with the 5’?3’ exoribonuclease XRN1 [56]. Contrary to the prevailing opinions, Zaccara et al. revealed that DF proteins bound the same m6A-marked mRNAs rather than different ones and the DF paralogs act redundantly in mediating mRNA degradation and cellular differentiation. Furthermore, they proposed a unified model that all m6A-marked mRNAs were subjected to the combined action of YTHDF proteins, which was proportional to the number of m6A sites [57]. The second group, the heterogeneous nuclear ribonucleoprotein (HNRNP) family, includes HNRNPC, HNRNPG, and HNRNPA2B1. Among them, HNRNPC mediates pre-mRNA processing through ‘the m6A-switch’ mechanism, wherein m6A alters the RNA structure to facilitate the binding [58]. Katherine and co-workers revealed an integrated mechanism of co-transcriptional m6A-mediated splicing regulation in which HNRNPG directly interacted with RNA polymerase II [59]. The third member in this family, termed as HNRNPA2B1, functions through directly binding primary miRNA to elicit alternative splicing effect. Meanwhile, its interaction with the microRNA Microprocessor complex protein DGCR8 promoted primary miRNA processing [60]. The third group of readers is the insulin-like growth factor 2 mRNA-binding protein family, IGF2BP1/2/3, possessing 4 repetitive KH domains. IGF2BPs specifically bind to m6A-marked RNA with KH3/4, enhancing the mRNA stability and facilitate the translation [61, 62]. Though the regulatory mechanism remains unraveled, previous study proved that YBX1 cooperates with IGF2BPs to stabilize m6A-tagged RNA [62]. Aside from the above three groups, novel readers are continuously being discovered. For example, PRRC2A (Proline rich coiled-coil 2A) is found to play an important role in oligodendrocyte specification through binding to m6A site on Olig2 mRNA [63].

Functions of m6A in mRNA fate

As mentioned above, writers and erasers act in methylation and demethylation, respectively. Readers preferentially recognize m6A modifications, and thus determine the fate of the methylated RNAs, including RNA splicing, exportation, translation, and stability (Fig. 1). For pre-mRNA splicing, the interaction between m6A regulators and splicing factors could affect the alternative splicing pattern, leading to exon skipping and abnormal transcripts. For nuclear export, several regulators have been verified to play a significant role. For translation, the m6A-mediated regulation is intricate and multi-layered, including direct and indirect mechanisms. As for mRNA stability, whether maintaining stability or promoting degradation depends on the readers, via specific pathways. And m6A modifications can enhance phase separation, which further determine the fate of RNAs.

Pre-mRNA splicing

Splicing is a critical step in post-transcriptional regulation, in which the alternatively removing of introns and joining exons produce diverse transcripts. m6A modification sites are spatially overlapping with mRNA splicing enhancer binding regions, thus regulate mRNA alternative splicing [17]. Precious studies have found that downregulation of m6A writers interferes splicing and gene expression [64, 65]. As noted, METTL16-dependent m6A in the U6 spliceosomal snRNA and 3'-UTR of mRNA impacts RNA splicing and stability [36, 66]. Meanwhile, demethylases also show significant influences in regulating splicing. As the preferential binding sites of FTO are adjacent to the alternative splicing exon and polyA site, the demethylation tends to inhibit recruitment of serine/arginine-rich splicing factor 2 (SRSF2) and induce exon 6 skipping [17, 67]. Also, suppression of ALKBH5 results in exon jumping in transcripts, which are rapidly degraded [68]. Additionally, ALKBH5 exerts its regulatory effect by promoting the phosphorylation of ASF/SF2, the hyperphosphorylated form of which is involved in splicing [41]. As mentioned before, hnRNPA2B1 gets access to target RNA via an “m6A switch” mechanism, then regulate RNA splicing in a METTL3-dependent way. Furthermore, loss of hnRNPC/hnRNPG will alter the splicing pattern [58,59,60]. Wen et al. identified that YTHDC1 modulates pre-mRNAs splicing through facilitating SRSF3 and repelling SRSF10 [69].

RNA nuclear export

After being fully processed, mRNAs are translocated into cytoplasm, where writers, erasers, readers all participate in [70]. The interaction between YTHDC1 and SRSF3 facilitates the export of RNA via modulating the contact between RNA and nuclear RNA export factor 1 (NXF1) [53]. FMRP, as a reader, is indispensable in the nuclear export mediated by Exportin 1 (XPO1) [71, 72]. ALKBH5 is involved in phosphorylation of ASF/SF2 and the hypophosphorylated ASF/SF2 facilitates mRNA export by mediating the interaction of the TAP-p15 complex and mRNA [73, 74], thus ALKBH5 is responsible for determining the subcellular location of mRNAs. Consistent with that, polyA RNA accumulation in the cytoplasm was observed in ALKBH5-deficient cells, attributed to the augmented nuclear RNA export [41].

RNA translation

m6A-related translation regulation plays a pivotal role in several cancer and some normal physiological processes. METTL3 can regulate translation in both methyltransferase catalytic -dependent and -independent manner. The former pattern is more common, in which METTL3 methylated mRNA and then readers mediated the specific regulation [75]. METTL3 also has impact on the biogenesis of ribosome via modulating the PES1 expression [75]. As for the indirect regulatory mechanism, METTL3 interacts with eIF3h to enhance translation and generates densely packed polyribosomes [76, 77], which is distinguished from the stress-inducing mechanism [78]. Similarly, Rui Su et al. discovered that METTL16 could promote translation by directly interacting with the eIF3a, eIF3b and rRNA, thereby facilitating the assembly of the translation-initiation complex in the cytosol [37]. It has been verified that the interaction of YTHDFs with translation machinery can enhance translation. Mechanistically, YTHDF1 facilitates the cap-dependent translation initiation by forming a loop structure with eIF4G and eIF3, consequently recruiting ribosomes [79]. In addition to collaborating with these translational factors, YTHDF1 could advance the expression level of eIF3C in an m6A-dependent manner [80]. Similarly, YTHDF1 knockdown leads to significant decrease of eIF3A and 3B in Merkel Cell Carcinoma [81]. Although eIF4 complex is necessary in typical translational initiation, YTHDF1 could provoke initiation in the absence of eIF4 complex, through eIF3A and 3B [81]. Zhou et al. observed that m6A abundance induced by heat shock conditions in 5'-UTR could promotes the initiation of cap-independent translation [78]. Later, Liu et al. revealed that the stress-induced m6A modification in the 5'-UTR promotes mRNA translation via binding to eIF3 independent of YTHDF1 [80]. Synergizing with YTHDF1, YTHDF3 promotes translation by interacting with 40 and 60 S ribosome subunits [52, 82]. YTHDC2, with RNA helicase activity, boosts translation efficiency but declines mRNA abundance [83, 84].

RNA stability

The mRNA stability governs the equilibrium of RNA metabolism and gene expression. While some studies support the negative correlation between m6A modification and mRNA stability [28, 85], existing experimental results indicating that m6A modification serves as a double-edged sword in regulating mRNA stability [61, 86, 87]. As a well-established regulator of RNA decomposition, YTHDF2 selectively binds to target mRNA via its C-terminal domain, and the N-terminal domain is responsible for localizing the YTHDF2-mRNA complex to RNA decay site, where the deadenylase complex CCR4-NOT was recruited [55, 88]. FTO can increase the stability of MYC mRNA by inhibiting the m6A-dependent RNA decay mediated by YTHDF2 [89]. YTHDF3 is in synergism with YTHDF2 to induce mRNA degradation [90]. And YTHDF1 was found to induce the degradation of MAT2A mRNA by recognizing its 3’-UTR m6A site [34]. In contrast to YTHDF2, readers IGF2BP1/2/3 could improve mRNA stability with its KH domain binding to m6A site under normal and stress conditions [61]. Additionally, FMRP and PRRC2A have also been proven to enhance mRNA stability in an m6A-dependent manner [86, 87]. Thus, some oncogenes with decreased m6A level were observed to be less stable.

Phase separation

Phase separation, especially liquid–liquid phase separation (LLPS), drives the formation of compartmentalization in a membraneless manner. It has been highly considered as a significant strategy for various biological reactions [91]. Since m6A can alter the charge, conformation and protein anchoring of modified RNAs, it can further regulate phase separation by influencing RNA-protein and RNA-RNA interactions. Several studies have verified that YTHDFs could lead to phase separation both in vivo and in vitro, closely correlated with the formation of stress granules, P granules and neuronal RNA granules [92,93,94]. The LCDs of YTHDFs can trigger phase separation without RNAs in vitro, but the direct binding between YTH domains and m6A sites is required for phase separation in vivo [92]. Recently, Jiong Li et al. revealed that YTHDF1 interacts with AGO2 to promote mRNA degradation through LLPS [95]. Also, the functions of YTHDC1 in bioprocesses are closely correlated with phase separation. YTHDC1 is reported to mediate chromatin remodeling via phase separation [96]. In mechanism, it promotes the demethylation of histone mark H3K9me2 by recruiting demethylase KDM3B [97]. YTHDC1 can recognize the m6A sites on lncRNA XIST and further recruit repressive proteins to induce gene silencing, which is supposed to be mediated by phase separation [20, 98]. Similarly, the function of YTHDC1 in alternative splicing is supposed to be modulated by phase separation [99].

Fig. 1
figure 1

Molecular composition and regulation mechanism of m6A methylation modification. m6A methylation is a dynamic and reversible process coordinated by methyltransferases (defined as “writers”, including METTL3, METTL14, WTAP, ZC3H13, HAKAI, VIRMA, and RBM15), demethylases (defined as “erasers”, FTO and ALKBH5), and “readers”, such as YTHDF1-3, YTHDC1, IGF2BPs, HNRNPC, HNRNPA2B1, and eIF3. These molecules recognize and bind to m6A-modified RNA and thus mediate RNA splicing, stability, translation, and RNA nuclear export

Role of m6A in hematopoietic malignancies

Normal hematopoiesis hinges on the balance between regeneration and differentiation of HSCs, which is under rigorous and elaborate control. Dysregulated HSCs will transform into LSCs, accounting for the occurrence of hematopoietic malignancies, as well as the poor prognosis and chemotherapeutic resistance. The m6A methylation is supposed to participate in almost every crucial process, and some underlying mechanisms have been illuminated (Table 1; Fig. 2). Importantly, previous studies revealed the therapeutic potential of several regulators. Small-molecule inhibitors of METTL3, FTO, ALKBH5 have recently been identified and have exhibited considerable anti-leukemia effects both in vitro and in mouse models (Table 2).

Table 1 The target genes, biological functions and mechanisms of RNA m6A methyltransferases, demethylases, and binding proteins in hematopoietic malignancies
Fig. 2
figure 2

Targets and molecular mechanisms of m6A regulators

METTL3

Given its vital role in maintaining the normal functions and quiescent state of HSCs, the depletion of METTL3 promotes HSCs differentiation and reduces cell proliferation (Fig. 3). On the contrary, METTL3 overexpression prohibits cell differentiation and triggers cell growth [100]. Via increasing the m6A level of MYC, BCL2 and PTEN, METTL3 facilitates their translation, thereby leading to augmented proliferation and reduced differentiation of AML cells [84]. Meanwhile, it was proved that overexpression of MYC could rescue the deficiency of METTL3 by maintaining symmetrical differentiation [119]. METTL3 associates with chromatin and migrates to transcriptional start site (TSS) of active genes, where CAATT-box binding protein CEBPZ was located. Promoter bound METTL3 initiates the m6A modification of the target mRNA, and subsequently induces the translation by relieving ribosome stagnation [101]. Moreover, METTL3 is supposed to regulate HSC generation via affecting endothelial-to-hematopoietic transition (EHT). Loss of METTL3 delays the YTHDF2-mediated degradation of Notch1a, thus activating Notch signaling pathway which hinders the transition of endothelium into HSCs [102]. In normal hematopoiesis, the expression of METTL3 was alleviated in mature differentiated myeloid cells on a regular basis. The abundance of METTL3 contributes to leukemogenesis and maintenance of the malignant proliferation and undifferentiated state of LSC. Besides, METTL3 has been validated to promote chemoresistance against AML. The downregulation of METTL3 in AML-MSCs upregulates AKT expression, enhances adipogenesis, and results in chemoresistance [120]. MEG3 could elevate expression of miR-493-5p which targeted METTL3/MYC axis, thus promotes the chemosensitivity of AML cells [121].

In addition to causal roles in AML, emerging studies have correlate METTL3 with the initiation and progression of ALL and CML. Ianniello et al. demonstrated that upregulated METTL3/METTL14 could drive the malignant proliferation of CML cells and mediate the resistance against TKIs [122]. METTL3 concurrent with facilitating chemoresistance and restraining autophagy via lowering PTEN mRNA stability in a YTHDF2-dependent manner, METTL3 also controls the progression of CML through m6A modification of lncRNA and the consequent modulation of miR-766-5p/CDKN1A axis [123]. The enrichment of METTL3 was observed in ETV6/RUNX1-positive ALL, while comparatively less expressed in recurrent patients [124, 125]. Besides, Liu and co-workers have unraveled the positive correlation between METTL3 gene polymorphism and the risk of pediatric ALL [126].

The therapeutic potential of METTL3 as an anti-leukemia target has elicited considerable interest, for exploring its inhibitors to intervene the proliferation, differentiation, and apoptosis of leukemia cells. Increasing researches revealed that METTL3 inhibitor treatment results in dose-dependent reduction in m6A level in several cell lines, without alteration in other RNA modifications [127]. Tzelepis et al. have discovered two selective inhibitors of METTL3, which dramatically decreased the expression of METTL3-mediated m6A proteins at the nanomolar level, such as SP1. And they remarkably suppressed tumor growth of in AML model. Throughout METTL3 inhibitors developed the most recently, STM2457 was testified to prolong survival in different mouse AML models [128]. Built upon the structural optimization of a series of METTL3 inhibitors, UZH2 was identified to potently inhibit the function of METTL3 [129].

METTL14

As a component of MTC, the expression pattern of METTL14 is similar to METTL3, which is enriched in HSCs (Fig. 3). A recent study displayed that in normal CD34 + HSCs, deficiency in METTL14 promotes differentiation, decreases colony formation, but has no obvious effects on cell growth and apoptosis [104]. Particularly, METTL14, negatively regulated by SPI1, plays a critical role in normal hematopoiesis by facilitating the expression of two oncogenic transcription factors, MYB and MYC [104]. Thus, METTL14 is indispensable for the self-renewal of LSCs and development of leukemia. METTL14 was found highly expressed in AML cells carrying t(11q23), t(15;17), or t(8;21), and loss of METTL14 significantly inhibits the proliferation and viability of these cells. Besides AML, high expression of METTL14 was also monitored in ALL and CML [125]. However, further explorations are requisite to understand its regulatory role in leukemogenesis and exploit new therapeutic targets.

WTAP

Up to now, it remains elusive whether WTAP participates in normal hematopoiesis and LSC self-renewal, but its association with leukemogenesis has been solidified. Several studies reported the highly expression of WTAP in AML, which is related with poor prognosis. Knockdown of WTAP inhibits proliferation and facilitates differentiation, suggesting that WTAP was an oncogene in AML [105, 106]. Further experiments revealed that WTAP could not execute its oncogenic role without METTL3, as WTAP failed to increase the proliferation level of leukemia cells with depressed METTL3 [130]. Particularly, WTAP plays a significant role in chemoresistance. In mechanism, deficiency in WTAP reduces the degradation of MYC mRNA in AML cells via a m6A-dependent manner [106]. WTAP knockdown increased sensitivity to chemotherapy drug daunorubicin of leukemia cells [105], while upregulation of WTAP promoted resistance to etoposide in AML [106]. Moreover, Hsp90 could prevent the degradation of WTAP in ubiquitin-proteasome pathway [106]. Shao et al. revealed the positive correlation between the WTAP and HIF1a, indicating that HIF1a may participate in the regulation of WTAP [131].

FTO

Distinct from methyltransferases, the demethylase FTO seems to play a minor role in normal HSCs [108]. However, FTO is engaged in the tumorigenesis and development of leukemia as an oncogene (Fig. 3). Inhibition of FTO attenuates LSC/LIC self-renewal by decreasing the expression of MYC and CEBPA [110]. On the contrary, the overexpression of FTO induces proliferation, curbs differentiation and apoptosis of AML cells, and promotes leukemogenesis in mice, highlighting its oncogenic role in AML [107]. High expression of FTO is found in specific AML subtypes by analyzing the whole genome of AML patients. In terms of the mechanism, FTO reduces expression of tumor suppressors RARA and ASB2 by impairing their mRNA stability, and thus facilitates the occurrence of leukemia [132]. Furthermore, overexpression of FTO contributes to TKI-resistance in leukemia cells via stabilizing MERTK and BCL2 mRNA. Thus, the combination of FTO inhibitors and TKIs could exhibit more favorable efficacy than TKI monotherapy for treating leukemia in mouse model [109].

These findings ignited scientists’ enthusiasm to explore therapeutic drugs targeting FTO. Rhein, the first naturally occurred FTO inhibitor, displays therapeutic efficacy in leukemia mice by competitively binding to the catalytic site of FTO [133]. Huang et al. discovered the MA, a nonsteroidal anti-inflammatory drug, selectively inhibits the demethylase activity of FTO [134]. Further research proved that MA2, the ester form of MA, could suppress glioblastoma progression [135]. MA derivative FB23-2 is also identified as selective inhibitor of FTO, and performs anti-leukemia functions in mouse AML model [136]. Another FTO inhibitor, R-2HG, exerts antitumor effects in AML by destabilizing the MYC/CEBPA mRNA [89]. Particularly, it was showed that R-2HG could effectively suppress aerobic glycolysis. And the underlying mechanism is disturbing the FTO-mediated post-transcriptional upregulation of critical glycolytic gene, PFKP and LDHB [108]. Su et al. found two small molecule FTO inhibitors, CS1 (bisantrene) and CS2 (brequinara), Which dramatically attenuate leukemia stem/initiating cell self-renewal and reprogram immune response by suppressing expression of immune checkpoint genes, especially LILRB4 [136]. Recently, Bai et al. have screened several acrylonitrile derivatives as potential FTO inhibitors. And they found that chlorine atom was involved in the binding between these small molecules and FTO [137]. Saikosaponin D is identified as an FTO-targeted drug to impair AML cells proliferation, inducing apoptosis and cell cycle arrest both in vitro and vivo, particularly in TKIs-resistant cells [138]. Besides, Wu, D et al. discovered that let-7b-5p mimics could downregulate the expression of FTO and thus upregulate c-MYC level in AML line cells [139].

ALKBH5

Despite dispensable in normal hematopoiesis and HSC functions, ALKBH5 is critical for the development and maintenance of LSCs (Fig. 3) [112]. Knockdown of ALKHB5 reduces proliferation and induces apoptosis of LSCs, attenuates its leukemogenic function in mice. For the mechanism, ALKBH5 enhances the expression of AXL by preventing the YTHDF2-medaited mRNA decay, and AXL is a receptor tyrosine kinase (RTK) phosphorylating FLT3 to accelerate development of AML [111, 135]. Also, ALKBH5 can stabilize TACC3 mRNA, a vital oncogene in multiple tumors, to promote self-renewal of LSC/LIC [135]. Meanwhile, ALKBH5 can induce AML chemoresistance by activating PI3K, MAPK, NF-kB, and JAK/STAT pathways, while KDM4C modulates the expression of ALKBH5 via promoting chromatin accessibility and recruiting MYC and Pol II to the promotor [111, 140]. Moreover, ALKBH5 can upregulate the expression of USP1, which mediates the glucocorticoid-resistance in T-ALL patients and cells via interacting with Aurora B [141]. These findings reveal the significance of ALKBH5 in the pathogenic process of leukemia. The abundance of ALKBH5 is found in AML patients with a normal karyotype, inv. [15], t(11q23), and t(8;21) and supposed to be related with poor prognosis.

Collectively, with a minor influence on normal hematopoiesis, ALKBH5 is considered as a crucial therapeutic target for leukemia. The crystallographic and biochemical studies indicated that the ALKBH5 inhibitors may be smaller in size than those for FTO, due to its smaller active cavity [142]. Selberg et al. assessed the antiproliferative effects of ALKBH5 inhibitors and discovered two compounds with potent inhibition against the proliferation of three leukemia cell lines, demonstrating the value of ALKBH5 inhibitor as an anti-leukemia strategy [143]. Le Zhang at al found that bioactive peptides could inhibit AML progression by reducing the ALKBH5-mediated m6A demethylation of EIF4EBP1 and MLST8 mRNAs, downregulating these two genes at both the RNA and protein levels [144].

Fig. 3
figure 3

m6A methyltransferases and demethylases in modulating normal and malignant hematopoiesis

YTHDF2

It has been confirmed that YTHDF2 is crucial for maintaining the quiescent stage of HSCs and the deletion of YTHDF2 induces HSCs expansion in umbilical cord blood of human and mouse (Fig. 4) [103, 113, 114]. YTHDF2-deficient HSCs from young mice fail upon serial transplantation and chronically activate proinflammatory pathways. Moreover, hematopoiesis-specific YTHDF2 deficiency gives rise to a progressive myeloid bias, including loss of lymphoid potential, HSC expansion, and failure to reconstitute multilineage hematopoiesis [145]. YTHDF2 suppresses HSC self-renewal by promoting the mRNA degradation of key transcription factors (e.g., Tal1), which are critical for stem cell self-renewal [145]. Also, it has been found that loss of YTHDF2 decreases the m6A-dependent degradation, and thus abnormally activates Wnt signaling which could enhance the HSCs regeneration [103]. Moreover, YTHDF2 also plays a vital role in the proliferation and functional integrity of LSCs. For instance, it could prevent LSCs from apoptosis via decreasing tumor necrosis factor (TNF) receptor 2 (TNFR2) [113]. YTHDF2-deficient AML cells display impaired proliferative ability, increased apoptosis rate and decreased engraftment capacity [113].

Other regulators

YTHDC1

The contributions of YTHDC1 in normal hematopoiesis and leukemogenesis have been illuminated (Fig. 4). Yue et al. revealed that YTHDC1 participates in maintenance of HSCs and self-renewal of LSCs. Knockdown of YTHDC1 notably suppressed the regeneration of LSCs and primary AML cells rather than HSCs. YTHDC1 regulates leukemogenesis via MCM4, a critical DNA replication regulator [115]. Yuanming et al. confirmed that YTHDC1 is essential in maintaining cell viability and undifferentiated form in AML cells. They proved that the formation of nuclear YTHDC1-m6A condensates (nYACs) mediated by LLPS enables YTHDC1 to protect some mRNAs, such as MYC mRNA, from being degraded by PAXT complex and exosome, thus facilitates the process of leukemia [146].

IGF2BPs

IGF2BPs is reported to be significant for myeloid leukemia cell survival in an m6A-dependent manner, by interacting with YBX1 and stabilizing m6A-tagged RNA (Fig. 4) [62]. IGF2BP1 is supposed to maintain the integral properties of LSC by upregulating a set of crucial regulators, including HOXB4, MYB and ALDH1A1 [116]. Loss of IGF2BP1 decreased tumorigenicity, induced apoptosis and differentiation, and increased sensitivity to chemotherapy of leukemia cells. Moreover, high expression of IGF2BP1 is correlative with poor prognosis in AML patients [116]. Recently, Nan Zhang proposed that IGF2BP3 is required in leukemogenesis by interacting with RCC2 mRNA. It is demonstrated that knockdown of IGF2BP3 decreases AML cell viability in vivo, while overexpression of IGF2BP3 promotes proliferation and tumorigenesis of AML [117].

RBM15

The expression of RBM15 during hematopoiesis and its suppressive effects on myeloid differentiation has been validated. The underlying mechanism may be that RBM15 stimulates Notch signaling through RBPJkappa to disturb differentiation [118]. Overexpression of PRMT1 in acute megakaryocytic leukemia cell lines can downregulate RBM15 protein level via promoting its methylation and ubiquitylation. Subsequently, the expressions of several megakaryopoiesis-related genes are enhanced, such as GATA1, RUNX1, TAL1 and c-MPL, which blocks the terminal differentiation of megakaryocyte then [147].

Fig. 4
figure 4

m6A readers in modulating normal and malignant hematopoiesis

Table 2 small-molecule inhibitors of m6A regulators

Conclusion

Accumulated evidences show that m6A modification the has broad influences on normal and malignant hematopoiesis, primarily by affecting mRNA stability and translation efficiency at the posttranslational level. It plays an important role in maintaining the normal functions of HSCs, promoting the occurrence and development of leukemia. Researchers are inspired to excavate the clinical potentials of m6A regulators as diagnostic biomarkers and therapeutic targets. However, the underlying rationales still remain unclear and the clinical applications require further investigations.

There are still challenges about the mechanism: (1) although it has been demonstrated that m6A modification affect RNA life through various pathway, it remains unclear how these selective effects are determined in different cellular environment, m6A-regulated phase separation provides a novel perspective to understand the specific effects; (2) following METTL3, METTL6 is identified to exert both methyltranferase activity-dependent and -independent functions, which inspires us to explore these regulators at a deeper level; (3) researchers have found that some regulators selectively function in either normal or malignant hematopoiesis while seem to be dispensable in the other process, the underlying rationale needs more exploration; (4) similar to other tumors, the existing studies of hematological show a relative bias toward writers and erasers, more attention is expected to be given to readers. Besides, emphasis shall be given to the interaction between m6A methylation and other epigenetic modifications.

With regard to the clinical applications, many opportunities and challenges exist: (1) The current m6A modification inhibitors and activators must be examined comprehensively with preclinical and clinical trials before clinical utilization. Actually, it takes several years and high cost for an anticancer drug into clinic use. Few of the currently available FTO inhibitors are limited by its poor sensitivity and/or selectivity; (2) similarly, whether m6A and its regulators can be used as potential biomarkers for diagnosis and prognosis of hematologic tumors need to be investigated thoroughly; (3) the potential interplay between m6A and ncRNAs provides a wide scope for future researches to explore more therapeutic targets; (4) traditional medicines and natural products have convincing safety validated by generations, and they are reliable sources of novel chemical structures. Moreover, AI-assisted approaches greatly improve the efficiency in screening, assessing and optimizing potential compounds [149].

Overall, previous progresses in m6A modification open up new avenues for future exploration. Given the significant role of RNA m6A in hematological malignancies, it is worthwhile to explore the therapeutic potentials and clinical benefits by targeting m6A regulators. We are convinced that the pathological mechanisms of hematological malignancies will be better understood and more feasible therapeutic strategies targeting m6A modification will be provided.

Availability of data and materials

Not applicable.

Abbreviations

3'UTRs:

3'untranslated regions

ADAM19:

A disintegrin and metallopeptidase domain 19

ALDH1A1:

Aldehyde dehydrogenase 1 family member A1

ALKBH5:

alkB homolog 5

AML:

Acute myeloid leukemia

ASB2:

Ankyrin repeat and SOCS box containing 2

ATRA:

All-trans-retinoic acid

AXL:

AXL receptor tyrosine kinase

BCL2:

B cell lymphoma 2

CCR4-NOT:

Glucose-repressible alcohol dehydrogenase transcriptional effector

CEBPA:

CCAAT enhancer binding protein alpha

CEBPZ:

CCAAT enhancer binding protein zeta

DNMT3A:

DNA methyltransferase 3 alpha

EHT:

Endothelial-to-hematopoietic transition

eIF:

Eukaryotic translation initiation factor

FMRP:

fragile X mental retardation protein

FOXM1:

Forkhead box protein M1

FTO:

Fat mass and obesity-associated protein

HIF:

Hypoxia-inducible factor

HNRNP:

heterogeneous nuclear ribonucleoprotein

HOXB4:

Homeobox B4

HSC:

hematopoietic stem cells

IGF2BP:

insulin-like growth factor 2 mRNA-binding protein

KDM4C:

Lysine demethylase 4 C

LDHB:

Lactate dehydrogenase B

LILRB4:

Leukocyte immunoglobulin like receptor B4

LSC:

leukemia stem cells

lncRNA:

long noncoding RNA

m6A:

N6-Methyladenosine

MA:

Meclofenamic acid

MCM4:

minichromosome maintenance proteins

METTL:

Methyltransferase-like

MERTK:

MER proto-oncogene, tyrosine kinase

MTC:

methyltransferase complex

MYB:

MYB proto-oncogene, transcription factor

MYC:

MYC proto-oncogene, bHLH transcription factor

NXF1:

nuclear RNA export factor 1

Notch1a:

Notch receptor 1a

pre-mRNA:

precursor mRNA

PES1:

pescadillo ribosomal biogenesis factor 1

PFKP:

Phosphofructokinase platelet

PRMT1:

protein arginine methyltransferase 1

PRRC2A:

proline rich coiled-coil 2 A

PTEN:

Phosphatase and tensin homolog

R-2HG:

R-2-hydroxyglutarate

RARA:

Retinoic acid receptor alpha

RBM15:

RNA-binding motif protein 1

SAM:

S-Adenosyl methionine

SPI1:

Spi-1 proto-oncogene

SRSF:

Serine and arginine-rich splicing factor

TACC3:

Transforming acidic coiled-coil containing protein 3

TKI:

Tyrosine kinase inhibitor

VCRs:

vertebrate-conserved regions

VIRMA:

Vir-like m6A methyltransferase-associated

WTAP:

Wilms tumor 1-associated protein

XIST:

X-inactive specific transcript

YAP:

yes-associated protein

YTH:

YT521-B homology

YTHDC1/2:

YTH domain-containing protein 1/2

YTHDF1/2/3:

YTH domain family protein 1/2/3

ZC3H13:

Zinc finger CCCH-type containing 13

ZCCHC4:

zinc finger CCHC-type containing 4

ZFD:

zinc finger domain

ZNF217:

Zinc finger protein 217

References

  1. Speck NA, Gilliland DG. Core-binding factors in haematopoiesis and leukaemia. Nat Rev Cancer. 2002;2:502–13.

    CAS  PubMed  Article  Google Scholar 

  2. N. Cancer Genome Atlas Research, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–2074.

  3. Dohner H, Weisdorf DJ, Bloomfield CD. Acute Myeloid Leukemia. N Engl J Med. 2015;373:1136–52.

    PubMed  Article  CAS  Google Scholar 

  4. Dimopoulos K, Gronbaek K. Epigenetic therapy in hematological cancers. APMIS. 2019;127:316–28.

    PubMed  Article  Google Scholar 

  5. Jones PA, Issa JP, Baylin S. Targeting the cancer epigenome for therapy. Nat Rev Genet. 2016;17:630–41.

    CAS  PubMed  Article  Google Scholar 

  6. Boccaletto P, et al. MODOMICS: a database of RNA modification pathways. 2017 update. Nucleic Acids Res. 2018;46:D303–7.

    PubMed  Article  CAS  Google Scholar 

  7. Meyer KD, et al. Comprehensive analysis of mRNA methylation reveals enrichment in 3’ UTRs and near stop codons. Cell. 2012;149:1635–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Dominissini D, et al. Topology of the human and mouse m(6)A RNA methylomes revealed by m(6)A-seq. Nature. 2012;485:201-U284.

    Article  CAS  Google Scholar 

  9. Linder B, et al. Single-nucleotide-resolution mapping of m6A and m6Am throughout the transcriptome. Nature Methods. 2015;12:767-U114.

    Article  CAS  Google Scholar 

  10. Fu Y, Dominissini D, Rechavi G, He C. Gene expression regulation mediated through reversible m(6)A RNA methylation. Nat Rev Genet. 2014;15:293–306.

    CAS  PubMed  Article  Google Scholar 

  11. Zuo X, et al. M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma. J Hematol Oncol. 2020;13:5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Ban Y, et al. LNCAROD is stabilized by m6A methylation and promotes cancer progression via forming a ternary complex with HSPA1A and YBX1 in head and neck squamous cell carcinoma. Mol Oncol. 2020;14:1282–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. Alarcon CR, Lee H, Goodarzi H, Halberg N, Tavazoie SF. N6-methyladenosine marks primary microRNAs for processing. Nature. 2015;519:482–5.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Di Timoteo G, et al. Modulation of circRNA Metabolism by m(6)A Modification. Cell Rep. 2020;31:107641.

    PubMed  Article  CAS  Google Scholar 

  15. Yang Y, et al. Glucose Is Involved in the Dynamic Regulation of m(6)A in Patients With Type 2 Diabetes. Journal of Clinical Endocrinology & Metabolism. 2019;104:665–73.

    Article  Google Scholar 

  16. Luo JY, Liu H, Luan SY, He CS, Li ZY. Aberrant Regulation of mRNA m(6)A Modification in Cancer Development. Int J Mol Sci. 2018;19:2515.

  17. Zhao X, et al. FTO-dependent demethylation of N6-methyladenosine regulates mRNA splicing and is required for adipogenesis. Cell Research. 2014;24:1403–19.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. Liu J, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10:93–5.

    CAS  PubMed  Article  Google Scholar 

  19. Ping XL, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24:177–89.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. Patil DP, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537:369–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. Yue Y, et al. VIRMA mediates preferential m(6)A mRNA methylation in 3’UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 2018;4:10.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA. 1997;3:1233–47.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Wang P, Doxtader KA, Nam Y. Structural Basis for Cooperative Function of Mettl3 and Mettl14 Methyltransferases. Mol Cell. 2016;63:306–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. Huang J, et al. Solution structure of the RNA recognition domain of METTL3-METTL14 N(6)-methyladenosine methyltransferase. Protein Cell. 2019;10:272–84.

    CAS  PubMed  Article  Google Scholar 

  25. Wang Z, et al. m(6) A deposition is regulated by PRMT1-mediated arginine methylation of METTL14 in its disordered C-terminal region. EMBO J. 2021;40:e106309.

  26. Sorci M, et al. METTL3 regulates WTAP protein homeostasis. Cell Death Dis. 2018;9:796.

  27. Moindrot B, et al. A Pooled shRNA Screen Identifies Rbm15, Spen, and Wtap as Factors Required for Xist RNA-Mediated Silencing. Cell Rep. 2015;12:562–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. Schwartz S, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5’ sites. Cell Rep. 2014;8:284–96.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Qian JY, et al. KIAA1429 acts as an oncogenic factor in breast cancer by regulating CDK1 in an N6-methyladenosine-independent manner. Oncogene. 2019;38:6123–41.

    CAS  PubMed  Article  Google Scholar 

  30. Wen J, et al. Zc3h13 Regulates Nuclear RNA m(6)A Methylation and Mouse Embryonic Stem Cell Self-Renewal. Mol Cell. 2018;69:1028-1038 e1026.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. Knuckles P, et al. Zc3h13/Flacc is required for adenosine methylation by bridging the mRNA-binding factor Rbm15/Spenito to the m(6)A machinery component Wtap/Fl(2)d. Genes Develop. 2018;32:415–29.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Mendel M, et al. Methylation of Structured RNA by the m(6)A Writer METTL16 Is Essential for Mouse Embryonic Development. Molecular Cell. 2018;71:986.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. Pendleton KE, et al. The U6 snRNA m(6)A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell. 2017;169:824.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Shima H, et al. Synthesis Is Regulated by Selective N-6-Adenosine Methylation and mRNA Degradation Involving METTL16 and YTHDC1. Cell Reports. 2017;21:3354–63.

    CAS  PubMed  Article  Google Scholar 

  35. Ruszkowska A, Ruszkowski M, Dauter Z, Brown JA. Structural insights into the RNA methyltransferase domain of METTL16. Sci Rep. 2018;8:5311.

  36. Aoyama T, Yamashita S, Tomita K. Mechanistic insights into m(6)A modification of U6 snRNA by human METTL16. Nucleic Acids Res. 2020;48:5157–68.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. Su R, et al. METTL16 exerts an m(6)A-independent function to facilitate translation and tumorigenesis. Nat Cell Biol. 2022;24:205–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. Pinto R, et al. The human methyltransferase ZCCHC4 catalyses N6-methyladenosine modification of 28S ribosomal RNA. Nucleic Acids Res. 2020;48:830–46.

    CAS  PubMed  Article  Google Scholar 

  39. Ren W, et al. Structure and regulation of ZCCHC4 in m(6)A-methylation of 28S rRNA. Nat Commun. 2019;10:5042.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. van Tran N, et al. The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 2019;47:7719–33.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. Zheng GQ, et al. ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse Fertility. Molecular Cell. 2013;49:18–29.

    CAS  PubMed  Article  Google Scholar 

  42. Jia GF, et al. N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nature Chemical Biology. 2011;7:885–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. Zhu CX, Yi CQ. Switching Demethylation Activities between AlkB Family RNA/DNA Demethylases through Exchange of Active-Site Residues. Angewandte Chemie-International Edition. 2014;53:3659–62.

    CAS  PubMed  Article  Google Scholar 

  44. Mauer J, et al. Reversible methylation of m(6)A(m) in the 5 ’ cap controls mRNA stability. Nature. 2017;541:371.

    CAS  PubMed  Article  Google Scholar 

  45. Wei JB, et al. Differential m(6)A, m(6)A(m), and m(1)A Demethylation Mediated by FTO in the Cell Nucleus and Cytoplasm. Molecular Cell. 2018;71:973-+.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Mauer J, Jaffrey SR. FTO, m(6) Am, and the hypothesis of reversible epitranscriptomic mRNA modifications. FEBS Lett. 2018;592:2012–2022.

  47. Zhang X, et al. Structural insights into FTO’s catalytic mechanism for the demethylation of multiple RNA substrates. Proc Natl Acad Sci U S A. 2019;116:2919–24.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. Ueda Y, et al. AlkB homolog 3-mediated tRNA demethylation promotes protein synthesis in cancer cells. Sci Rep. 2017;7:42271.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation. Nature Reviews Molecular Cell Biology. 2019;20:608–24.

    CAS  PubMed  Article  Google Scholar 

  50. Liao S, Sun H, Xu C, Domain YTH. A Family of N(6)-methyladenosine (m(6)A) Readers. Genomics Proteomics Bioinformatics. 2018;16:99–107.

    PubMed  PubMed Central  Article  Google Scholar 

  51. Jain D, et al. ketu mutant mice uncover an essential meiotic function for the ancient RNA helicase YTHDC2. Elife. 2018;7:e30919.

  52. Shi H, et al. YTHDF3 facilitates translation and decay of N(6)-methyladenosine-modified RNA. Cell Res. 2017;27:315–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Roundtree IA, et al. YTHDC1 mediates nuclear export of N(6)‑methyl‑adenosine methylated mRNAs. Elife. 2017;6:e31311.

  54. Xiao W, et al. Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Mol Cell. 2016;61:507–19.

    CAS  PubMed  Article  Google Scholar 

  55. Du H, et al. YTHDF2 destabilizes m(6)A‑containing RNA through direct recruitment of the CCR4‑NOT deadenylase complex. Nat Commun. 2016;7:12626.

  56. Li L, et al. The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m(6)A recognition. Mol Cell. 2022;82:1678-1690 e1612.

    CAS  PubMed  Article  Google Scholar 

  57. Zaccara S, Jaffrey SR. A Unified Model for the Function of YTHDF Proteins in Regulating m(6)A-Modified mRNA. Cell. 2020;181:1582-1595 e1518.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Liu N, et al. N-6-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015;518:560–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Zhou KI, et al. Regulation of Co-transcriptional Pre-mRNA Splicing by m(6)A through the Low-Complexity Protein hnRNPG. Mol Cell. 2019;76:70-81 e79.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Alarcon CR, et al. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell. 2015;162:1299–308.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. Huang H, et al. Recognition of RNA N(6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Feng MD, et al. YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m(6)A-dependent manner. Blood. 2021;138:71–85.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. Wu R, et al. A novel m(6)A reader Prrc2a controls oligodendroglial specification and myelination. Cell Res. 2019;29:23–41.

    CAS  PubMed  Article  Google Scholar 

  64. Taketo K, et al. The epitranscriptome m6A writer METTL3 promotes chemo- and radioresistance in pancreatic cancer cells. Int J Oncol. 2018;52:621–9.

    PubMed  Google Scholar 

  65. Dominissini D, et al. Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq. Nature. 2012;485:201–6.

    CAS  PubMed  Article  Google Scholar 

  66. Pendleton KE, et al. The U6 snRNA m(6)A Methyltransferase METTL16 Regulates SAM Synthetase Intron Retention. Cell. 2017;169:824-835 e814.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Bartosovic M, et al. N6-methyladenosine demethylase FTO targets pre-mRNAs and regulates alternative splicing and 3’-end processing. Nucleic Acids Res. 2017;45:11356–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Tang C, et al. ALKBH5-dependent m6A demethylation controls splicing and stability of long 3’-UTR mRNAs in male germ cells. Proc Natl Acad Sci U S A. 2018;115:E325–33.

    PubMed  Google Scholar 

  69. Roundtree IA, He C. Nuclear m(6)A Reader YTHDC1 Regulates mRNA Splicing. Trends Genet. 2016;32:320–1.

    CAS  PubMed  Article  Google Scholar 

  70. Fustin JM, et al. RNA-methylation-dependent RNA processing controls the speed of the circadian clock. Cell. 2013;155:793–806.

    CAS  PubMed  Article  Google Scholar 

  71. Edens BM, et al. FMRP Modulates Neural Differentiation through m(6)A-Dependent mRNA Nuclear Export. Cell Reports. 2019;28:845.

    CAS  PubMed  Article  Google Scholar 

  72. Hsu PJ, et al. The RNA-binding protein FMRP facilitates the nuclear export of N (6)-methyladenosine-containing mRNAs. J Biol Chem. 2019;294:19889–95.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. Li X, Manley JL. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Cell. 2005;122:365–78.

    CAS  PubMed  Article  Google Scholar 

  74. Michlewski G, Sanford JR, Caceres JF. The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1. Mol Cell. 2008;30:179–89.

    CAS  PubMed  Article  Google Scholar 

  75. Ianniello Z, et al. New insight into the catalytic ‑dependent and ‑independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia. Cell Death Dis. 2021;12:870.

  76. Choe J, et al. mRNA circularization by METTL3-eIF3h enhances translation and promotes oncogenesis. Nature. 2018;561:556–60.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. Lin S, Choe J, Du P, Triboulet R, Gregory RI. The m(6)A Methyltransferase METTL3 Promotes Translation in Human Cancer Cells. Mol Cell. 2016;62:335–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. Zhou J, et al. Dynamic m(6)A mRNA methylation directs translational control of heat shock response. Nature. 2015;526:591–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. Wang X, et al. N(6)-methyladenosine Modulates Messenger RNA Translation Efficiency. Cell. 2015;161:1388–99.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Liu T, et al. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 2020;48:3816–31.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  81. Orouji E, Peitsch WK, Orouji A, Houben R, Utikal J. Oncogenic Role of an Epigenetic Reader of m(6)A RNA Modification: YTHDF1 in Merkel Cell Carcinoma. Cancers (Basel). 2020;12:202.

  82. Li A, et al. Cytoplasmic m(6)A reader YTHDF3 promotes mRNA translation. Cell Res. 2017;27:444–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Kretschmer J, et al. The m(6)A reader protein YTHDC2 interacts with the small ribosomal subunit and the 5 ‘-3 ’ exoribonuclease XRN1. Rna. 2018;24:1339–50.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. Wojtas MN, et al. Regulation of m(6) A Transcripts by the 3’ -> 5’ RNA Helicase YTHDC2 Is Essential for a Successful Meiotic Program in the Mammalian Germline. Molecular Cell. 2017;68:374.

    CAS  PubMed  Article  Google Scholar 

  85. Geula S, et al. Stem cells. m6A mRNA methylation facilitates resolution of naive pluripotency toward differentiation. Science. 2015;347:1002–6.

    CAS  PubMed  Article  Google Scholar 

  86. Edupuganti RR, et al. N(6)-methyladenosine (m(6)A) recruits and repels proteins to regulate mRNA homeostasis. Nat Struct Mol Biol. 2017;24:870–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. Zhang F, et al. Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets. Hum Mol Genet. 2018;27:3936–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang X, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–20.

    PubMed  Article  CAS  Google Scholar 

  89. Su R, et al. R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m(6)A/MYC/CEBPA Signaling. Cell. 2018;172:90-105 e123.

    CAS  PubMed  Article  Google Scholar 

  90. Shi HL, et al. YTHDF3 facilitates translation and decay of N-6-methyladenosine-modified RNA. Cell Research. 2017;27:315–28.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. Banani SF, Lee HO, Hyman AA. Rosen, Biomolecular condensates: organizers of cellular biochemistry. Nat Rev Mol Cell Biol. 2017;18:285–98.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. Gao Y, et al. Multivalent m(6)A motifs promote phase separation of YTHDF proteins. Cell Res. 2019;29:767–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. Ries RJ, et al. m(6)A enhances the phase separation potential of mRNA. Nature. 2019;571:424–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Fu Y, Zhuang X. m(6)A-binding YTHDF proteins promote stress granule formation. Nat Chem Biol. 2020;16:955–63.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  95. Li J, et al. YTHDF1 promotes mRNA degradation via YTHDF1-AGO2 interaction and phase separation. Cell Prolif. 2022;55:e13157.

    CAS  PubMed  Google Scholar 

  96. Peng L, Li EM, Xu LY. From start to end: Phase separation and transcriptional regulation. Biochim Biophys Acta Gene Regul Mech. 2020;1863:194641.

    CAS  PubMed  Article  Google Scholar 

  97. Li Y, et al. N(6)-Methyladenosine co-transcriptionally directs the demethylation of histone H3K9me2. Nat Genet. 2020;52:870–7.

    CAS  PubMed  Article  Google Scholar 

  98. Cerase A, et al. Phase separation drives X-chromosome inactivation: a hypothesis. Nat Struct Mol Biol. 2019;26:331–4.

    CAS  PubMed  Article  Google Scholar 

  99. Ninomiya K, et al. m(6) A modification of HSATIII lncRNAs regulates temperature-dependent splicing. EMBO J. 2021;40:e107976.

  100. Vu LP, et al. The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med. 2017;23:1369–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Barbieri I, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m(6)A-dependent translation control. Nature. 2017;552:126.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. Zhang C, et al. m(6)A modulates haematopoietic stem and progenitor cell specification. Nature. 2017;549:273–6.

    CAS  PubMed  Article  Google Scholar 

  103. Wang H, et al. Loss of YTHDF2-mediated m(6)A-dependent mRNA clearance facilitates hematopoietic stem cell regeneration. Cell Research. 2018;28:1035–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. Weng H, et al. METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification. Cell Stem Cell. 2018;22:191-205 e199.

    CAS  PubMed  Article  Google Scholar 

  105. Naren D, et al. High Wilms’ tumor 1 associating protein expression predicts poor prognosis in acute myeloid leukemia and regulates m(6)A methylation of MYC mRNA. J Cancer Res Clin Oncol. 2021;147:33–47.

    CAS  PubMed  Article  Google Scholar 

  106. Bansal H, et al. WTAP is a novel oncogenic protein in acute myeloid leukemia (vol 28, pg 1171, 2014). Leukemia. 2014;28:2427–2427.

    CAS  Article  Google Scholar 

  107. Li Z, et al. Plays an Oncogenic Role in Acute Myeloid Leukemia as a N(6)-Methyladenosine RNA Demethylase. Cancer Cell. 2017;31:127–41.

    PubMed  Article  CAS  Google Scholar 

  108. Qing Y, et al. R-2-hydroxyglutarate attenuates aerobic glycolysis in leukemia by targeting the FTO/m(6)A/PFKP/LDHB axis. Mol Cell. 2021;81:922-939 e929.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. Yan F, et al. A dynamic N(6)-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors. Cell Res. 2018;28:1062–76.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  110. Su R, et al. Targeting FTO Suppresses Cancer Stem Cell Maintenance and Immune Evasion. Cancer Cell. 2020;38:79-96 e11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. Wang JZ, et al. Leukemogenic Chromatin Alterations Promote AML Leukemia Stem Cells via a KDM4C-ALKBH5-AXL Signaling Axis. Cell Stem Cell. 2020;27:81.

    PubMed  Article  CAS  Google Scholar 

  112. Shen C, et al. RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia. Cell Stem Cell. 2020;27:64-+.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Paris J, et al. Targeting the RNA m(6)A Reader YTHDF2 Selectively Compromises Cancer Stem Cells in Acute Myeloid Leukemia. Cell Stem Cell. 2019;25:137-148 e136.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. Li Z, et al. Suppression of m(6)A reader Ythdf2 promotes hematopoietic stem cell expansion. Cell Res. 2018;28:904–17.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. Sheng Y, et al. A Critical Role of Nuclear m6A Reader YTHDC1 in Leukemogenesis by Regulating MCM Complex‑Mediated DNA Replication. Blood. 2021;138:2838–52.

  116. Elcheva IA, et al. RNA-binding protein IGF2BP1 maintains leukemia stem cell properties by regulating HOXB4, MYB, and ALDH1A1. Leukemia. 2020;34:1354–63.

    CAS  PubMed  Article  Google Scholar 

  117. Zhang N, et al. The m6A reader IGF2BP3 promotes acute myeloid leukemia progression by enhancing RCC2 stability. Exp Mol Med. 2022;54:194–205.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. Ma X, et al. Rbm15 modulates Notch-induced transcriptional activation and affects myeloid differentiation. Mol Cell Biol. 2007;27:3056–64.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. Cheng Y, et al. m(6)A RNA Methylation Maintains Hematopoietic Stem Cell Identity and Symmetric Commitment. Cell Rep. 2019;28:1703-1716 e1706.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. Pan ZP, et al. METTL3 mediates bone marrow mesenchymal stem cell adipogenesis to promote chemoresistance in acute myeloid leukaemia. FEBS Open Bio. 2021;11:1659–72.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. Wang A, et al. Tumor-suppressive MEG3 induces microRNA-493-5p expression to reduce arabinocytosine chemoresistance of acute myeloid leukemia cells by downregulating the METTL3/MYC axis. J Transl Med. 2022;20:288.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. Ianniello Z, et al. New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia. Cell Death Dis. 2021;12:870.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. Yao FY, et al. m(6)A Modification of lncRNA NEAT1 Regulates Chronic Myelocytic Leukemia Progression via miR-766-5p/CDKN1A Axis. Front Oncol. 2021;11:679634.

    PubMed  PubMed Central  Article  Google Scholar 

  124. Wang Y, et al. The gene expression level of m6A catalytic enzymes is increased in ETV6/RUNX1-positive acute lymphoblastic leukemia. International Journal of Laboratory Hematology. 2021;43:E89–91.

    PubMed  Google Scholar 

  125. Sun C, Chang L, Liu C, Chen X, Zhu X. The study of METTL3 and METTL14 expressions in childhood ETV6/RUNX1-positive acute lymphoblastic leukemia. Mol Genet Genomic Med. 2019;7:e00933.

    PubMed  PubMed Central  Google Scholar 

  126. Liu X, et al. Novel Associations Between METTL3 Gene Polymorphisms and Pediatric Acute Lymphoblastic Leukemia: A Five-Center Case-Control Study. Front Oncol. 2021;11:635251.

    PubMed  PubMed Central  Article  Google Scholar 

  127. Moroz‑Omori EV, et al. METTL3 Inhibitors for Epitranscriptomic Modulation of Cellular Processes. Chem Med Chem. 2021;16:3035–43.

  128. Yankova E, et al. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature. 2021;593:597–601.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. Dolbois A, et al. 1,4,9-Triazaspiro[5.5]undecan-2-one Derivatives as Potent and Selective METTL3 Inhibitors. J Med Chem. 2021;64:12738–60.

    CAS  PubMed  Article  Google Scholar 

  130. Sorci M, et al. METTL3 regulates WTAP protein homeostasis. Cell Death Dis. 2018;9:796.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  131. Shao YL, Chen Z, Wang LL, Liu DH, Gao XN. [The Relationship between HIF1alpha and WTAP Expression Level in t(8;21) Acute Myeloid Leukemia]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021;29:1424–8.

    PubMed  Google Scholar 

  132. Guibal FC, et al. ASB-2 inhibits growth and promotes commitment in myeloid leukemia cells. J Biol Chem. 2002;277:218–24.

    CAS  PubMed  Article  Google Scholar 

  133. Chen B, et al. Development of cell-active N6-methyladenosine RNA demethylase FTO inhibitor. J Am Chem Soc. 2012;134:17963–71.

    CAS  PubMed  Article  Google Scholar 

  134. Huang Y, et al. Meclofenamic acid selectively inhibits FTO demethylation of m6A over ALKBH5. Nucleic Acids Res. 2015;43:373–84.

    CAS  PubMed  Article  Google Scholar 

  135. Cui Q, et al. m(6)A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Rep. 2017;18:2622–34.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. Huang Y, et al. Small-Molecule Targeting of Oncogenic FTO Demethylase in Acute Myeloid Leukemia. Cancer Cell. 2019;35:677-691 e610.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. Bai N, et al. The role of chlorine atom on the binding between acrylonitrile derivatives and fat mass and obesity-associated protein. J Mol Recognit. 2021;34:e2880.

    CAS  PubMed  Article  Google Scholar 

  138. Sun K, et al. Saikosaponin D exhibits anti-leukemic activity by targeting FTO/m(6)A signaling. Theranostics. 2021;11:5831–46.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. Wu DS, et al. [Hsa-let-7b-5p Inhibits Proliferation of Human Leukemia THP-1 Cells via FTO/m(6)A/MYC Signaling Pathway]. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2020;28:1873–9.

    PubMed  Google Scholar 

  140. Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer. 2014;14:769–85.

    CAS  PubMed  Article  Google Scholar 

  141. Gong H, Liu L, Cui L, Ma H, Shen L. ALKBH5-mediated m6A-demethylation of USP1 regulated T-cell acute lymphoblastic leukemia cell glucocorticoid resistance by Aurora B. Mol Carcinog. 2021;60:644–57.

    CAS  PubMed  Article  Google Scholar 

  142. You Y, et al. Recent Advances of m6A Demethylases Inhibitors and Their Biological Functions in Human Diseases. Int J Mol Sci. 2022;23:5815.

  143. Selberg S, Seli N, Kankuri E, Karelson M. Rational Design of Novel Anticancer Small-Molecule RNA m6A Demethylase ALKBH5 Inhibitors. ACS Omega. 2021;6:13310–20.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Zhang L, Su X. Bioactive peptide inhibits acute myeloid leukemia cell proliferation by downregulating ALKBH5-mediated m(6)A demethylation of EIF4EBP1 and MLST8 mRNA. Cell Oncol (Dordr). 2022;45:355–65.

    CAS  Article  Google Scholar 

  145. Mapperley C, et al. The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function. J Exp Med. 2021;218:e20200829.

  146. Cheng YM, et al. N-6-Methyladenosine on mRNA facilitates a phase-separated nuclear body that suppresses myeloid leukemic differentiation. Cancer Cell. 2021;39:958.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Zhang L, et al. Cross‑talk between PRMT1‑mediated methylation and ubiquitylation on RBM15 controls RNA splicing. Elife. 2015;4:e07938.

  148. Tzelepis K et al. Pharmacological Inhibition of the RNA m(6)a Writer METTL3 As a Novel Therapeutic Strategy for Acute Myeloid Leukemia. Blood. 2019;134:403.

  149. Deng LJ, et al. m6A modification: recent advances, anticancer targeted drug discovery and beyond. Mol Cancer. 2022;21:52.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

We apologize to the colleagues whose work could not be cited due to space constraints.

Funding

This study was supported by the Youth Innovation Project of University of Science and Technology of China (WK9110000203, WK9110000204) and the Natural Science Foundation of Anhui Province (2008085MH241).

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Wei-Wei Liu and Hao Wang collected the related literature. Wei-Wei Liu and Xiao-Yu Zhu wrote the manuscript. Hao Wang and Xiao-Yu Zhu participated in the design of the review and revised the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Hao Wang or Xiao-Yu Zhu.

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Liu, WW., Wang, H. & Zhu, XY. Physio-pathological effects of N6-methyladenosine and its therapeutic implications in leukemia. Biomark Res 10, 64 (2022). https://doi.org/10.1186/s40364-022-00410-3

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Keywords

  • N6-methyladenosine
  • Hematopoietic stem cells
  • Hematopoiesis
  • Leukemia