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

Overview

MeSH Major

  • Anthracyclines
  • Chromatin Assembly and Disassembly
  • DNA (Cytosine-5-)-Methyltransferase
  • Drug Resistance, Neoplasm
  • Leukemia, Myeloid, Acute

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.

publication date

  • November 2017

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5677536

Digital Object Identifier (DOI)

  • 10.1038/nm.4416

PubMed ID

  • 28920958

Additional Document Info

start page

  • 1369

end page

  • 1376

volume

  • 23

number

  • 11