The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells Journal Article

   

Authors:	Vu, L. P.; Pickering, B. F.; Cheng, Y.; Zaccara, S.; Nguyen, D.; Minuesa, G.; Chou, T.; Chow, A.; Saletore, Y.; MacKay, M.; Schulman, J.; Famulare, C.; Patel, M.; Klimek, V. M.; Garrett-Bakelman, F. E.; Melnick, A.; Carroll, M.; Mason, C. E.; Jaffrey, S. R.; Kharas, M. G.
Article Title:	The N(6)-methyladenosine (m(6)A)-forming enzyme METTL3 controls myeloid differentiation of normal hematopoietic and leukemia cells
Abstract:	N 6 -methyladenosine (m 6 A) is an abundant nucleotide modification in mRNA that is required for the differentiation of mouse embryonic stem cells. However, it remains unknown whether the m 6 A modification controls the differentiation of normal and/or malignant myeloid hematopoietic cells. Here we show that shRNA-mediated depletion of the m 6 A-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 m 6 A coupled with ribosome profiling reveals that m 6 A 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.
Journal Title:	Nature Medicine
Volume:	23
Issue:	11
ISSN:	1078-8956
Publisher:	Nature Publishing Group
Date Published:	2017-11-01
Start Page:	1369
End Page:	1376
Language:	English
DOI:	10.1038/nm.4416
PROVIDER:	scopus
PMCID:	PMC5677536
PUBMED:	28920958
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85033234178&doi=10.1038%2fnm.4416&partnerID=40&md5=bc6bc4f68e75c2386ca2c9b5ce300c52
Notes:	Article -- Export Date: 4 December 2017 -- Source: Scopus

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