The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal and leukemia cells

By L. Vu, Brian F. Pickering, Yuanming Cheng, S. Zaccara, D. Nguyen, Gerard Minuesa, T. Chou, Arthur Chow, Yogesh Saletore, M. Mackay and 10 more. Nature Medicine, 2017

888 citations recorded by the source corpus.

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m6A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m6A-forming enzyme METTL3 in human hematopoietic stem/progenitor cells (HSPCs) promotes cell differentiation, coupled with reduced cell proliferation. Conversely, overexpression of wild-type METTL3, but not of a catalytically inactive form of METTL3, inhibits cell differentiation and increases cell growth. METTL3 mRNA and protein are expressed more abundantly in acute myeloid leukemia (AML) cells than in healthy HSPCs or other types of tumor cells. Furthermore, METTL3 depletion in human myeloid leukemia cell lines induces cell differentiation and apoptosis and delays leukemia progression in recipient mice in vivo. Single-nucleotide-resolution mapping of m6A coupled with ribosome profiling reveals that m6A promotes the translation of c-MYC, BCL2 and PTEN mRNAs in the human acute myeloid leukemia MOLM-13 cell line. Moreover, loss of METTL3 leads to increased levels of phosphorylated AKT, which contributes to the differentiation-promoting effects of METTL3 depletion. Overall, these results provide a rationale for the therapeutic targeting of METTL3 in myeloid leukemia.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/89a82522a223306649af43ea901990d2b387861a

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In Molecular Biology

1. Chuan He
2. Samie R. Jaffrey
3. S. Zaccara
4. Hailing Shi
5. Jiangbo W
6. Jianjun Chen
7. B. Zhao
8. Zhike Lu

Citations in the corpus

• Targeting FTO suppresses cancer stem cell maintenance and immune evasion (2020, neutral): “Similar to FTO, m6A writers (METTL3/14) also target MYC and play oncogenic roles in AML (Barbieri et al., 2017; Vu et al., 2017; Weng et al., 2018), likely through distinct mechanisms (Deng et al.”
• METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification (2017, background): “A recent report showed that METTL3 also plays an oncogenic role in AML (Vu et al., 2017).”
• A Unified Model for the Function of YTHDF Proteins in Regulating m6A-Modified mRNA (2020, methodology): “The N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.”
• Accurate detection of m6A RNA modifications in native RNA sequences (2019, background): “BACKGROUND In the last few years, our ability to map RNA modifications transcriptome-wide has revolutionized our understanding of how these chemical entities shape cellular processes, modulate cancer risk, and govern cellular fate [1–4].”
• Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia (2019, background): “METTL3 and METTL14, the m6A methyltransferases, have been reported to control and/or maintain myeloid leukemia, highlighting their oncogenic roles in leukemogenesis (Barbieri et al., 2017; Vu et al., 2017; Weng et al., 2018).”