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

TitleThe N6-methyladenosine (m6A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsVu LP, Pickering BF, Cheng Y, Zaccara S, Nguyen D, Minuesa G, Chou T, Chow A, Saletore Y, MacKay M, Schulman J, Famulare C, Patel M, Klimek VM, Garrett-Bakelman FE, Melnick A, Carroll M, Mason CE, Jaffrey SR, Kharas MG
JournalNat Med
Volume23
Issue11
Pagination1369-1376
Date Published2017 Nov
ISSN1546-170X
KeywordsAdenosine, Bone Marrow Cells, Cell Differentiation, Cells, Cultured, Clustered Regularly Interspaced Short Palindromic Repeats, Humans, Leukemia, Myeloid, Acute, Methyltransferases, Tumor Cells, Cultured
Abstract

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.

DOI10.1038/nm.4416
Alternate JournalNat. Med.
PubMed ID28920958
PubMed Central IDPMC5677536
Grant ListP30 CA016672 / CA / NCI NIH HHS / United States
T32 CA062948 / CA / NCI NIH HHS / United States
R01 CA186702 / CA / NCI NIH HHS / United States
R01 DK101989 / DK / NIDDK NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA193842 / CA / NCI NIH HHS / United States
F32 CA221104 / CA / NCI NIH HHS / United States