Acute myeloid leukemia (AML)
AML is an extremely aggressive blood cancer that poses a life-threatening risk without adequate treatment. Despite advancements in risk assessment and therapeutic approaches, the 5-year survival rate for AML patients remains below 30%. There is a critical need for deeper comprehension of the underlying mechanisms of AML progression to develop potential treatments. AML represents the most prevalent form of leukemia in adults, comprising approximately 80% of cases. In the United States, the AML patient population reached 73,168 in 2020, with a yearly age-adjusted incidence rate of 4.3 cases per 100,000 individuals. The incidence of AML increases with age, and the median age at diagnosis is a crucial factor in understanding its prevalence. AML is responsible for about 2% of all cancer-related deaths in the UK, accounting for approximately 2,700 deaths annually.45,46
Recent studies underscore the significance of m6A RNA modification in cancer, particularly in AML progression. This modification profoundly influences the behavior of LSCs and extends beyond AML to various cancers, promoting tumor progression and drug resistance. For example, overexpression of m6A demethylase in relapse samples increases drug resistance in AML cells. Additionally, m6A readers play a role in promoting AML. The m6A methylase participates in various biological processes such as mammalian development, tumor generation, immunity, metastasis, stem cell renewal, and fat differentiation.47–49 Understanding the intricate relationship between m6A and AML offers valuable insights into potential therapeutic targets and prognostic indicators for this hematopoietic malignancy. Identifying the principal regulators of m6A modifications in AML could lead to enhanced therapeutic approaches for patients with this disease.
Recent research has explored the complex connection between m6A writers and the development of AML. METTL3 and METTL14, acting as key “writers”, assume pivotal roles in governing RNA epigenetics. In AML, these writers exert significant influence over various stages of leukemia development.50,51 Enhanced m6A modification, mediated by METTL3, disrupts key genes involved in AML initiation and progression. Additionally, METTL14 and WTAP, another essential m6A writer, show similar implications in AML pathogenesis (Table 1).37,40,52–86 Dysregulation of m6A writers in AML not only reveals molecular mechanisms but also presents potential therapeutic targets. Targeting these m6A writers may provide novel strategies for AML treatment by modulating RNA epigenetic landscapes. As our understanding of the intricate interplay between m6A writers and AML deepens, it opens avenues for developing targeted therapies aimed at disrupting aberrant RNA modifications associated with leukemia. Recent research highlights METTL3’s dual role in cancer. Traditionally known as a methyltransferase contributing to cancer progression through its methyltransferase activity, there is emerging evidence of an additional methyltransferase-independent function of cytoplasmic METTL3. This alternative mechanism is linked to promoting cancer advancement. Notably, METTL3’s cytoplasmic expression, regardless of its methyltransferase activity, plays a significant role in various facets of tumor progression, facilitating tumorigenesis, cell proliferation, invasion, migration, and accelerating the cell cycle. The use of KH12, a potent METTL3 degrader, has shown promise in reducing m6A levels in MOLM-13 cells, leading to anti-AML effects by lowering c-MYC protein levels.87METTL3 contributes to tumor progression by stabilizing lncRNA PSMA3-AS1, a recognized promoter of tumor advancement. PSMA3-AS1 influences FLT3-ITD+ AML by targeting miR-20a-5p, which regulates the expression of ATG16L1, a down-regulated mRNA in AML that impacts disease progression. This study integrates bioinformatics analysis, in vitro, and in vivo experiments to confirm METTL3 and PSMA3-AS1’s regulatory roles in the disease process. Furthermore, METTL3’s role in stabilizing PSMA3-AS1 suggests a potential cause for its increased expression. These findings offer valuable insights, serving as a foundation for tailoring targeted drugs to address FLT3-ITD AML.52METTL3, a methyltransferase-like 3, significantly influences the progression and chemoresistance of AML by impacting bone marrow mesenchymal stem cells (BMMSCs). Research has revealed diminished METTL3 expression in AML BMMSCs. In vivo experiments using mice with METTL3 depletion in BMMSCs showed elevated bone marrow adiposity, accelerated AML advancement, and increased resistance to cytarabine chemotherapy. METTL3 deletion in BMMSCs significantly increased adipogenesis of BMMSCs, linked to m6A-dependent decrease in AKT1 expression, a serine/threonine kinase 1 within the AKT pathway. This process promotes chemoresistance in AML. Targeting METTL3-mediated BMMSC adipogenesis could serve as a therapeutic approach for AML.53 Aberrant expression of circular RNAs (circRNAs) has been shown to influence AML progression. The novel circRNA, Circ_0001187, contributes to poor prognosis by being downregulated in AML patients. Knockdown of Circ_0001187 promotes AML cell proliferation and inhibits apoptosis, while overexpression has the opposite effect. Circ_0001187 reduces mRNA m6A modification by promoting the degradation of METTL3 protein. It acts as a competitive endogenous RNA, sequestering miR-499a-5p to upregulate RNF113A expression, which mediates METTL3 ubiquitin/proteasome-dependent degradation. Additionally, low Circ_0001187 expression is influenced by histone acetylation and promoter DNA methylation. These results indicate that Circ_0001187 acts as a crucial tumor suppressor in AML via the miR-499a-5p/RNF113A/METTL3 axis.54 In one study, the WTAP-SUCLG2-AS1-miR-17-5p-JAK1 pathway was identified as a crucial regulatory mechanism in AML development. Overexpressing SUCLG2-AS1 inhibited AML cell growth, migration, and invasion while enhancing apoptosis. SUCLG2-AS1 acts as a competitive endogenous RNA by sponging miR-17-5p, resulting in underexpression of JAK1. Additionally, WTAP was found to regulate m6A RNA methylation on SUCLG2-AS1 within AML cells, with increased WTAP levels linked to poor prognosis.55 Another study focused on hypoxia-inducible factor 1α (HIF1α) in t(8;21) AML. They found that HIF1α, known for its abnormal overexpression in this type of leukemia, acts as an oncogene by stimulating the expression of WTAP. WTAP overexpression alters the distribution of m6A on a transcriptome-wide scale, contributing to enhanced cell proliferation in this leukemia subtype. Research also revealed that elevated WTAP expression is linked to adverse prognosis in t(8;21) AML patients. Silencing WTAP hindered leukemia cell proliferation, triggered apoptosis, and facilitated cell differentiation. Mechanistically, HIF1α was found to activate WTAP transcription by directly binding to the hypoxia-response element in the gene’s promoter region. Targeting the HIF1α-WTAP axis, either pharmacologically or genetically, led to a reduction in m6A levels within the transcript of lysine demethylase 4B (KDM4B). This resulted in enhanced degradation of KDM4B, associated with reduced KDM4B expression and elevated levels of trimethylation of histone H3 at lysine 9. Suppression of KDM4B inhibited the growth of leukemia cells both in cell cultures and in murine models. In summary, the study emphasizes that HIF1α-mediated elevation of WTAP amplifies the malignant characteristics of leukemia cells. Moreover, it establishes a connection between m6A RNA methylation and histone methylation, demonstrating how the HIF1α-WTAP pathway influences the translation of m6A-dependent KDM4B, thereby affecting the overall development of t(8;21) AML.56
Table 1m6A modification in acute leukemia (AML & ALL)
Cancer type | m6A modifiers | Regulation/Role in cancer | Biological functions | Mechanisms | Potential clinical application | Ref |
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AML | METTL3 | Oncogene | METTL3 has the potential to enhance the stability of PSMA3-AS1 RNA. PSMA3-AS1 might contribute to the progression of FLT3-ITD+ AML by regulating autophagy levels through the miR-20a-5p/ATG16L1 pathway. | METTL3/PSMA3-AS1/miR-20a-5p/FLT3-ITD+ PSMA3-AS1/FLT3-ITD+ miR-20a-5p/ATG16L1 | Prompt screening and tailored therapy of FLT3-ITD+ AML | 52 |
AML | METTL3 | Oncogene | The downregulation of AKT1 expression in BMMSCs leads to a significant increase in adipogenesis. This downregulation occurs in an m6A-dependent manner, highlighting the role of m6A modification in modulating AKT1 levels. | METTL3/AKT1 | Targeting METTL3 modification as a therapeutic strategy in AML patient | 53 |
AML | METTL3 | Oncogene | Circ_0001187 diminishes mRNA m6A modification levels in AML cells by degrading the METTL3 protein. | miR-499a-5p/RNF113A/METTL3 | Potential therapeutic targeting of Circ _0001187 as a tumor suppressor in AML patient | 54 |
AML | METTL3 | Oncogene | METTL3 was increased in AML cells, leading to induction of cell proliferation and inhibition of cell differentiation. | METTL3/c-MYC/BCL2/PTEN | Therapeutic targeting of METTL3 in AML | 37 |
AML | METTL3 | Oncogene | METTL3 induces proliferation and suppresses differentiation in AML cells. Downregulation of METTL3 leads to cell cycle arrest and causes leukemia cells to differentiate. | CEBPZ/METTL3/SP1 | Potential therapeutic target for AML | 77 |
AML | METTL14 | Oncogene | METTL14 can suppress the differentiation of normal myeloid cells and is essential for the progress and maintenance of AML via m6A modifications. | SPI1-METTL14- MYB/MYC | Targeting METTL14 as an effective therapeutic method to treat METTL14-high AMLs | 78 |
AML | WTAP | Oncogene | The expression of WTAP is increased in AML patients and its overexpression can be correlated with poor prognosis. | WTAP/SUCLG2-AS1/miR-17-5p/JAK1 | Novel therapeutic target for AML treatment | 55 |
AML | WTAP | Oncogene | HIF1α promotes the expression of WTAP which markedly alters the transcriptome-wide m6A distribution and enhances cell proliferation in AML. WTAP is overexpressed and predicts poor prognosis in AML patients. | HIF1α/WTAP | – | 56 |
AML | WTAP | Oncogene | WTAP promotes cell proliferation, tumorigenesis, and chemoresistance of AML. | WTAP/MYC | Novel prognostic marker and new treatment target for AML patient | 79 |
AML | WTAP | Oncogene | miR-550-1 can suppress tumor progression that is downregulated in AML. miR-550-1 reduces the WWTR1 stability by the reduction in m6A levels through targeting WTAP. | miR-550-1/WTAP/WWTR1/BCL-2 miR-550-1/WTAP/WWTR1/CDK6/Rb/E2F1 | Upregulation of miR-550-1 can be used as a valuable therapeutic strategy in AML | 80 |
AML | WTAP | Oncogene | WTAP is upregulated in AML cells due to both decrease and increase of METTL3, which has oncogenic function only in the presence of METTL3. | METTL3/WTAP | – | 81 |
AML | WTAP | Oncogene | WTAP promotes cell proliferation and chemoresistance and inhibits differentiation | Not available | A promising therapeutic target in AML | 82 |
AML | FTO | Oncogene | Elevated FTO expression in relapse samples contributes to drug resistance in AML cells both in vivo and in vitro | FTO/FOXO3 | Potential therapeutic target of the FTO-m6A-FOXO3 axis in AML patients | 63 |
AML | FTO | Oncogene | FTO is overexpressed in t(8;21) AML, which is positively linked with AML1-ETO. Furthermore, FTO induces the expression of AML1-ETO by suppressing YTHDF2-mediated AML1-ETO mRNA decay. Deletion of FTO significantly inhibits cell proliferation, enhances cell differentiation, and contributes to chemoresistance. | AML1-ETO/FTO/IGFBP2 | Therapeutic target of AML1-ETO/FTO/IGFBP2 pathway in t(8;21) patients with resistance to Ara-C | 64 |
AML | FTO | Oncogene | BM-MSCs-isolated exosomes transport FTO, thereby enhancing the cancer aggressiveness, stem cell characteristics, and resistance to Cytosine arabinoside (Ara-C) chemotherapy in AML cells. | BM-MSCs-derived FTO-exo/lncRNA GLCC1/IGF2BP1/c-Myc | Potential biomarkers for the diagnosis and therapy of AML patients | 65 |
AML | FTO | Oncogene | SsD suppresses AML cell proliferation and induces apoptosis and cell cycle arrest by targeting FTO/m6A signaling. | Not available | Therapeutic targeting of FTO/m6A and the clinical potential of Saikosaponin in AML patients | 57 |
AML | FTO | Oncogene | FTO is highly expressed in AML and reduces m6A levels in ASB2 and RARA mRNA, thereby promoting leukemic oncogene-mediated cell transformation and leukemogenesis, and suppressing all-trans-retinoic acid (ATRA)-induced AML cell differentiation. | FTO/ASB2, RARA | A promising therapeutic strategy by targeting FTO to treat leukemia | 58 |
AML | FTO | Oncogene | R-2HG disrupted the post-transcriptional enhancement of PFKP and LDHB expression (two vital glycolytic genes), mediated by FTO/m6A/YTHDF2, thus reducing aerobic glycolysis in leukemia. | FTO/m6A/PFKP/LDHB | Clinical application of potent FTO inhibitors for cancer therapy | 59 |
AML | FTO | Oncogene | FTO promotes leukemogenesis. FTO inhibitors namely FB23 and FB23-2, suppress proliferation, induce differentiation, and promote apoptosis in human AML cells. | Not available | Therapeutic targeting FTO by small-molecule inhibitors for potential treatment of AML | 60 |
AML | ALKBH5 | Oncogene | ALKBH5 is regulated by chromatin state alteration during leukemogenesis of AML and is required for maintaining LSC function and tumor development. | KDM4C, MYB, Pol II/ALKBH5/AXL | The therapeutic target of ALKBH5 for specific targeting LSCs | 61 |
AML | ALKBH5 | Oncogene | The expression of ALKBH5 is increased in AML which correlates with poor prognosis. ALKBH5 is essential for the progression and maintenance of AML and self-renewal of leukemia stem/initiating cells (LSCs/LICs). | ALKBH5/TACC3 | The therapeutic potential of targeting ALKBH5/m6A axis for the treatment of AML | 62 |
AML | YTHDC1 | Oncogene | YTHDC1 interacted with HOXB-AS3, controlling its expression. Elevated levels of either YTHDC1 or HOXB-AS3 stimulated the growth of THP-1 cells and LSCs while hindering their apoptosis leading to an escalation in the count of LSCs in the blood and bone marrow of AML mice. | YTHDC1/HOXB-AS3 | Novel perspective for treatment of AML patients | 72 |
AML | YTHDC1 | Oncogene | YTHDC1 is overexpressed in AML and is involved in the proliferation and survival of AML cells, as well as the self-renewal of leukemia stem cells (LSCs) in mice | YTHDC1/MCM4 | Therapeutic potential of targeting YTHDC1 for the treatment of AML patients | 83 |
AML | YTHDC1 | Oncogene | nYACs prevent m6A-mRNA degradation by PAXT complex and exosome-related RNAs and also induce mRNA stability, AML cell survival, and undifferentiated state. | YTHDC1-m6A condensates (nYACs) | – | 84 |
AML | YTHDF1 | Oncogene | The expression of YTHDF1 is increased in human AML samples, particularly in LSC. YTHDF1 facilitates the translation of cyclin E2. Knockdown of YTHDF1 diminishes the self-renewal ability and proliferation of AML cells. | YTHDC1/cyclin E2 | A potential therapeutic target of YTHDF1 for the treatment of patients with AML | 69 |
AML | YTHDF2 | Oncogene | The level of YTHDF2 is overexpressed in AML patients, particularly in relapsed patients, and has a tumorigenic function in AML. | YTHDF2/miR-126 | reduction of YTHDF2 enhances HSC expansion and this makes it an ideal candidate for AML treatment | 66 |
AML | YTHDF2 | Oncogene | YTHDF2 expression is increased in t (8; 21)-type AML patients, and knockdown of YTHDF2 inhibits tumor cell proliferation in vitro and in vivo. | AML1/ETO-HIF1α loop/YTHDF2/TNFRSF1b | – | 68 |
AML | YTHDF2 | Oncogene | YTHDF2 is overexpressed in AML patients which contributes to the disease initiation and progression. In addition, YTHDF2 participates in the general integrity of LSCs function. | YTHDF2/TNFR2 | Inhibition of YTHDF2 as a unique therapeutic target to target LSCs and augment HSCs | 67 |
AML | IGF2BP1 | Oncogene | IGF2BP1 promotes cell proliferation and chemoresistance and inhibits differentiation in AML cells. | IGF2BP1/ALDH1A1, HOXB4, MYB | Therapeutic potential of targeting IGF2BP1 for the treatment of AML patients | 85 |
AML | IGF2BP2 | Oncogene | level of IGF2BP2 is increased in AML, which correlates with a poor prognosis. IGF2BP2 facilitates the progression of AML and enhances the self-renewal capacity of leukemia stem or initiation cells by controlling the expression of crucial targets such as MYC, GPT2, and SLC1A5 involved in glutamine metabolism pathways. | IGF2BP2/MYC, GPT2, and SLC1A5 | The potential of targeting IGF2BP2 as a novel strategy for the treatment of AML patients | 70 |
AML | IGF2BP3 | Oncogene | IGF2BP3 is increased in AML and required for the survival of AML cells. Deletion of IGF2BP3 inhibits apoptosis and decreases the proliferation of AML cells in vitro and in vivo. | IGF2BP3/RCC2 | Therapeutic potential of targeting IGF2BP3 for the treatment of AML patients | 71 |
AML | YBX1/IGF2BPs | Oncogene | YBX1 expression level is upregulated in myeloid leukemia cells, which maintains AML cell survival. YBX1 deficiency promotes apoptosis and induces differentiation while decreasing the proliferation of AML cells in vitro and in vivo. Furthermore, YBX1 through interacting with IGF2BPs maintains m6A-modified RNA. | YBX1/MYC/BCL2 (mRNA) | The therapeutic targeting of YBX1 in myeloid leukemia | 86 |
ALL | METTL3/METTL14 | – | METTL3 and METTL14 reduction indicate a possible role in the pathogenesis and development of E/R-positive pediatric ALL. | Not available | New prognostic factors and targeted therapy in E/R-positive ALL relapse patients | 73 |
ALL | Writers/Erasers | Oncogene | Elevated mRNA expression level of m6A writers (like METTL3, METTL14, WTAP) and m6A erasers (like FTO and ALKBH5) led to increased disease burden in patients with ALL. | Not available | – | 74 |
ALL | ALKBH5 | Oncogene | ALKBH5 increased USP1 mRNA stability and decreased m6A levels, which led to upregulation of USP1 and further promoted T-ALL development and chemoresistance. | ALKBH5/USP1/Aurora B | Potential biomarker for the chemoresistance treatment of T-ALL | 40 |
ALL | FTO | Oncogene | FTO bound IRF8 mRNA and leading mRNA degradation, and reduced level of IRF8 accelerates the advancement T-ALL. | FTO/IRF8 | Targeted therapy for T-ALL patients | 75 |
ALL | IGF2BP2 | Oncogene | IGF2BP2 is necessary to T-ALL cell proliferation via binding to T-ALL oncogene NOTCH1. | IGF2BP2/NOTCH1 | Targeted therapy for T-ALL patients | 76 |
Reversible m6A modifications involve demethylases, specifically FTO and ALKBH5, known as “eraser” complexes. These complexes have been extensively studied in leukemia, particularly in AML. Inhibiting ALKBH5, an m6A eraser, effectively hampers AML development and curtails leukemia stem cell self-renewal.57–62 The challenge of high relapse rates in AML, often attributed to chemotherapy resistance, was investigated using MeRIP-seq analysis on complete remission and relapse samples. The findings reveal dysregulated m6A methylation as a key factor in this process, with hypomethylated RNAs associated with altered cell differentiation. Notably, the m6A demethylase FTO exhibited heightened expression in relapse samples, contributing to increased drug resistance observed both in vivo and in vitro experiments. Knockdown of FTO resulted in enhanced cellular differentiation, particularly towards granulocytic and myeloid lineages, following treatment with cytarabine (Ara-C). The research identified FOXO3 as a downstream target of FTO, and decreased hypomethylation of FOXO3 mRNA resulted in reduced expression, hindering cell differentiation. The FTO-m6A-FOXO3 axis emerged as a central regulatory pathway influencing chemotherapy resistance in AML, emphasizing FTO as a promising therapeutic target.63 A separate investigation delved into the chromosomal abnormality t(8;21)(q22;q22) in AML, leading to the formation of the AML1-ETO fusion protein. Despite the favorable prognosis associated with t(8;21) AML, 30–50% of patients experience relapse and drug resistance. The role of m6A in AML development and its connection with AML1-ETO and m6A-related enzymes remains unclear. The research aimed to investigate the interplay between FTO and AML1-ETO, an enzyme responsible for m6A demethylation. In t(8;21) AML, FTO exhibits heightened expression, particularly among individuals with primary refractory disease. An affirmative regulatory loop has been identified between AML1-ETO and FTO. AML1-ETO enhances the expression of FTO by PU.1-mediated suppression of FTO transcription. Concurrently, FTO augments AML1-ETO expression while impeding YTHDF2-mediated degradation of AML1-ETO mRNA. Suppressing FTO activity inhibited cellular growth, enhanced cellular differentiation, and rendered t(8;21) AML cells sensitive to Ara-C. FTO operates through the regulation of its mRNA targets, particularly insulin-like growth factor binding protein 2 (IGFBP2), via an m6A-mediated mechanism. Targeting the AML1-ETO/FTO/IGFBP2 circuitry offers therapeutic potential for addressing resistance to Ara-C in patients with t(8;21) AML.64 Another study investigated the effects of exosomes isolated from mesenchymal stem cells in the bone marrow (BM-MSCs) containing FTO on AML. Previous research associated AML progression and chemotherapy resistance with exosomes derived from BM-MSCs, but the specific functions and molecular mechanisms remained unclear. The study aimed to explore the impact of FTO-carrying exosomes derived from BM-MSCs on the characteristics of AML cells. Findings indicated that exosomes originating from BM-MSCs and containing FTO enhanced cancer aggressiveness, stem cell properties, and resistance to the chemotherapy drug Ara-C in AML cells. This study identified that FTO-exosome-mediated demethylation of m6A modifications occurred in an lncRNA known as Glycolysis-associated lncRNA of colorectal cancer (GLCC1), leading to increased stability and expression. Conversely, GLCC1 functions as a driver oncogene, promoting cellular expansion and bolstering resistance to Ara-C in AML cells. Additional investigations revealed that demethylated GLCC1 served as a scaffold, facilitating the assembly of the IGF2BP1-c-Myc complex and activating subsequent c-Myc-associated signaling pathways that promote tumor growth. Silencing experiments validated that the enhancing effects of FTO-exosomes derived from BM-MSCs on cancer aggressiveness and drug resistance in AML cells depended on the presence of GLCC1 and c-Myc. In conclusion, the study provided insights into the molecular mechanisms of AML aggressiveness and chemoresistance enhanced by FTO-exosomes derived from BM-MSCs, highlighting the potential of targeting the GLCC1-IGF2BP1-c-Myc axis for AML diagnosis and therapy in clinical settings.65 In a study addressing chemotherapy challenges in AML patients, researchers investigated FTO’s role and the influence of the inhibitor Rhein on multidrug-resistant AML. They employed the Cell Counting Kit-8 reagent to evaluate Rhein’s impact on cell growth, migration, and apoptosis in AML cells, including those resistant to multiple drugs. Results revealed FTO overexpression in multidrug-resistant AML. Rhein demonstrated significant dose- and time-dependent inhibitory effects on proliferation and migration, induced apoptosis, and inhibited the AKT/mTOR pathways, even in resistant cells. Combining low doses of Rhein with azacitidine sensitized certain AML cells to chemotherapy. Overall, Rhein appears promising for treating multidrug-resistant AML by suppressing growth, inducing apoptosis, and enhancing chemotherapy sensitivity, offering a potential therapeutic option for such challenging cases.88
Numerous investigations have highlighted the pivotal role of m6A-associated genes in regulating AML initiation, progression, and drug resistance, while also demonstrating their significance in normal hematopoiesis. The involvement of m6A in interacting with “reader” proteins, including YTHDC1, HNRNPA2B1, and HNRNPC in the nucleus, and YTHDF1-3, IGF2BP1-3, and EIF3b in the cytoplasm, regulates processes such as splicing, translation, nuclear retention, and mRNA stability. Several of these readers, notably IGF2BP2, YTHDF2, and YTHDC1, exhibit oncogenic characteristics in AML. In continuation of this discussion, these findings are depicted in Table 1. Subsequently, we delved into elucidating these studies. For instance, YTHDF2 contributes to AML progression by enhancing miR-126 expression, a promoter of AML advancement and LSC self-renewal. Enhancing YTHDF2 inhibition promotes the expansion of HSCs, rendering it a promising candidate for AML treatment.66 In addition, YTHDF2 is responsible for reducing the lifespan of different m6A transcripts, contributing to the functionality of LSCs. This includes transcripts such as the tumor necrosis factor receptor TNFRSF2, whose increased expression in YTHDF2-deficient LSCs primes the cells for apoptosis. Interestingly, YTHDF2 does not play a critical role in normal HSC function; instead, its absence augments HSC activity. Consequently, YTHDF2 is recognized as an exceptional therapeutic target, where its inhibition selectively targets LSCs while fostering the proliferation of HSCs.67 The subtype of AML characterized by the t(8;21)(q22;q22.1) translocation, accounting for 4 to 8% of cases, represents a predominant category within AML and is characterized by frequent genetic abnormalities. YTHDF2 demonstrates overexpression in patients with t(8;21) AML, which correlates with an increased risk of relapse and inferior relapse-free survival.68YTHDF1, recognized as an oncogene in AML, affects AML through the translation of Cyclin E2, and Tegaserod can block its oncogenic activity.69IGF2BP2, highly expressed in AML, especially in LSCs, regulates glutamine metabolism as an m6A reader, making it a potential therapeutic target.70IGF2BP3, specifically overexpressed in AML, plays a critical role in cell survival through interaction with regulator of chromosome condensation 2 mRNA and maintenance of m6A-modified RNA expression.71YTHDC1, which enhances LSC self-renewal in AML, increases the expression of HOXB-AS3 spliceosome NR_033205.1 via m6A modification, offering new insights for AML treatment.72
Acute lymphoid leukemia (ALL)
ALL, a specific type of acute leukemia, entails widespread growth, extensive infiltration, and suppression of regular hematopoiesis.89 ALL is the most prevalent cancer in children under 15 years of age, amounting to 25% of such diagnoses.90 There are two primary classifications of ALL based on the immune cell phenotype: B-cell ALL, the predominant type, and T-cell ALL, which is generally known for its heightened aggressiveness.91 About 20–30% of ALL cases in adults and approximately 3–5% in children are characterized by the BCR-ABL fusion gene (BCR-ABL+ ALL). This subtype shows limited responsiveness to conventional chemotherapy, increases the risk of relapse, and is linked to an exceptionally poor outlook.92
Recent research uncovered the involvement of m6A modifications in the development of pediatric ALL harboring the ETV6/RUNX1 (E/R)-positive fusion gene, which is detected in approximately 25% of pediatric B-cell ALL cases. Sun et al.73 conducted a comparative analysis of METTL3 and METTL14 levels using RT-PCR (reverse transcription polymerase chain reaction) in a cohort of 37 pediatric patients with E/R-positive ALL, alongside six control subjects. They discovered a significant reduction in the expression levels of METTL3 and METTL14 in E/R-positive ALL compared to the control group, suggesting a potential contribution to both the onset and advancement of E/R-positive ALL. Another study found upregulation of m6A-modified methylases (METTL3, METTL14, and WTAP) and demethylases (ALKBH5 and FTO) in pediatric patients with E/R-positive ALL, based on an investigation into the expression levels of m6A catalytic enzyme genes in 33 such patients.74 Delving into various ALL subtypes is imperative to acquire a comprehensive understanding of the complete mechanism underlying m6A epigenetic modification in ALL.
Recent research indicated that ubiquitin-specific proteases (USPs) are implicated in T-cell ALL development and resistance to chemotherapy. Increased USP1 expression has been observed in glucocorticoid-resistant T-cell ALL patients and glucocorticoid-resistant cell line (CEM-C1) cells, correlating with a poor prognosis in T-cell ALL cases. Knockdown of USP1 heightened the sensitivity of CEM-C1 cells to dexamethasone, leading to decreased cell invasion, augmented apoptosis, and enhanced glucocorticoid receptor expression. USP1 modulates T-cell ALL chemoresistance through its interaction with and deubiquitination of Aurora B. ALKBH5, an m6A eraser, upregulated USP1 expression by reducing m6A levels and increasing mRNA stability in the USP1 transcript. The investigation confirmed that ALKBH5 downregulation decreased USP1 and Aurora B expression, thus promoting dexamethasone sensitivity, apoptosis, glucocorticoid receptor expression, and inhibiting cell invasion in CEM-C1 cells. Furthermore, experiments conducted in vivo using mice demonstrated that the intravenous injection of sh-USP1 notably suppressed tumor growth, resulting in prolonged survival. These findings offer valuable insights for clinical research on tumor treatment.93 Another study revealed that FTO, an m6A demethylase, plays a role in the progression of T-cell ALL by binding to m6A sites in the 3′ untranslated region of interferon regulatory factor 8 (IRF8) mRNA, leading to mRNA degradation through m6A modification. IRF8, a crucial transcription factor in determining hematological lineage commitment and capable of inhibiting T-cell ALL, is abnormally suppressed in T-cell ALL. Targeting the FTO-IRF8 axis in therapy, by inhibiting FTO’s demethylase activity, significantly reduces leukemic cell proliferation and extends the survival of mice with T-cell ALL by restoring IRF8 expression.75
In a related investigation, Feng et al.76 explored the function of the m6A reader IGF2BP2 in T-cell ALL. Their research provided evidence indicating that the increased expression of IGF2BP2 plays a critical role in promoting tumor cell proliferation in T-cell ALL, facilitated by its interaction with the NOTCH1 oncogene. A decrease in the expression level of IGF2BP2 resulted in extended survival in a human T-cell ALL xenograft model. Moreover, the development of the IGF2BP2 inhibitor JX5 effectively suppressed NOTCH1 activation and the progression of T-cell ALL, suggesting potential therapeutic benefits for T-cell ALL treatment.