TitleThe N-methyladenosine (mA)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsVu, Ly P., Pickering Brian F., Cheng Yuanming, Zaccara Sara, Nguyen Diu, Minuesa Gerard, Chou Timothy, Chow Arthur, Saletore Yogesh, MacKay Matthew, Schulman Jessica, Famulare Christopher, Patel Minal, Klimek Virginia M., Garrett-Bakelman Francine E., Melnick Ari, Carroll Martin, Mason Christopher E., Jaffrey Samie R., and Kharas Michael G.
JournalNat Med
Date Published2017 Nov
KeywordsAdenosine, Bone Marrow Cells, Cell Differentiation, Cells, Cultured, Clustered Regularly Interspaced Short Palindromic Repeats, Humans, Leukemia, Myeloid, Acute, Methyltransferases, Tumor Cells, Cultured

<p>N-methyladenosine (mA) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the mA modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the mA-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 mA coupled with ribosome profiling reveals that mA 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.</p>

Alternate JournalNat Med
PubMed ID28920958
PubMed Central IDPMC5677536
Grant ListF32 CA221104 / CA / NCI NIH HHS / United States
R01 CA186702 / CA / NCI NIH HHS / United States
T32 CA062948 / CA / NCI NIH HHS / United States