METTL3 Increases m⁶A to Block Differentiation and Promote Leukemogenesis

The reversible mRNA nucleotide modification N⁶-methyladenosine (m⁶A) is essential for mouse embryonic stem cell differentiation, but its role in normal and malignant myeloid hematopoietic cells is not clear. The METTL3 methyltransferase is responsible for forming m⁶A, prompting Vu, Pickering, Cheng, and colleagues to investigate the effects of METTL3 depletion in CD34⁺ hematopoietic stem/progenitor cells (HSPC). METTL3 depletion globally reduced m⁶A levels as expected, suppressed cell growth, and increased differentiation. Conversely, overexpression of wild-type METTL3, but not catalytically inactive METTL3, suppressed myeloid differentiation and enhanced proliferation and colony formation. METTL3 expression was upregulated in human acute myeloid leukemia (AML) samples compared with other tumor types and HSPCs, consistent with the dysregulated myeloid differentiation observed in AML. Further, METTL3 depletion delayed leukemogenesis in vivo, indicating a role for METTL3 and m⁶A in promoting AML. Single-nucleotide resolution mapping of m⁶A in an AML cell line to identify methylated mRNAs found that m⁶A sites were highly enriched near stop codons, and METTL3 depletion increased the abundance of transcripts with m⁶A sites, suggesting that m⁶A destabilizes mRNA. Ribosome profiling revealed that m⁶A regulated translation efficiency to promote translation of MYC, BCL2, and PTEN mRNAs in AML cells. Further, METTL3 suppressed AKT phosphorylation to inhibit differentiation. Catalytically dead METTL3 also reduced phospho-AKT levels, suggesting an m⁶A-independent mechanism. Taken together, these results indicate that increased m⁶A levels in AML suppress differentiation to promote leukemogenesis, and these findings suggest the potential for therapeutic targeting of METTL3 in myeloid malignancies.

Vu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, et al. The N⁶-methyladenosine (m⁶A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells. Nat Med 2017 Sep 18 [Epub ahead of print].

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