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Nat Med. 2017 Nov;23(11):1369-1376. doi: 10.1038/nm.4416. Epub 2017 Sep 18.

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

Author information

1
Molecular Pharmacology Program, Center for Cell Engineering, Center for Stem Cell Biology, Center for Experimental Therapeutics, Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
2
Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York, USA.
3
Department of Physiology and Biophysics, Weill Cornell Medicine, Cornell University, New York, New York, USA.
4
Hematologic Oncology Tissue Bank, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
5
Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
6
Memorial Sloan Kettering Cancer Center, Department of Medicine, Leukemia Service, New York, New York, USA.
7
Department of Medicine and Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, USA.
8
Division of Hematology and Medical Oncology, Department of Medicine and Department of Pharmacology, Weill Cornell Medicine, Cornell University, New York, New York, USA.
9
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
10
The HRH Prince Alwaleed Bin Talal Bin Abdulaziz Alsaud Institute for Computational Biomedicine, Weill Cornell Medicine, New York, New York, USA.
11
The Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York, USA.

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.

PMID:
28920958
PMCID:
PMC5677536
DOI:
10.1038/nm.4416
[Indexed for MEDLINE]
Free PMC Article

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