METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m6A Modification

Cell Stem Cell. 2018 Feb 1;22(2):191-205.e9. doi: 10.1016/j.stem.2017.11.016. Epub 2017 Dec 28.

Abstract

N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs), plays critical roles in many bioprocesses. However, its functions in normal and malignant hematopoiesis remain elusive. Here, we report that METTL14, a key component of the m6A methyltransferase complex, is highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukemia (AML) cells carrying t(11q23), t(15;17), or t(8;21) and is downregulated during myeloid differentiation. Silencing of METTL14 promotes terminal myeloid differentiation of normal HSPCs and AML cells and inhibits AML cell survival/proliferation. METTL14 is required for development and maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs). Mechanistically, METTL14 exerts its oncogenic role by regulating its mRNA targets (e.g., MYB and MYC) through m6A modification, while the protein itself is negatively regulated by SPI1. Collectively, our results reveal the SPI1-METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis and highlight the critical roles of METTL14 and m6A modification in normal and malignant hematopoiesis.

Keywords: HSC; HSPCs; LSCs/LICs; METTL14; MYB; MYC; N(6)-methyladenosine modification; SPI1; acute myeloid leukemia; myeloid differentiation block.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / metabolism
  • Animals
  • Carcinogenesis / genetics*
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Cell Differentiation*
  • Cell Proliferation
  • Cell Survival
  • Down-Regulation / genetics
  • Gene Expression Regulation, Leukemic
  • HEK293 Cells
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology*
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / pathology
  • Methyltransferases / genetics
  • Methyltransferases / metabolism*
  • Mice, Inbred C57BL
  • Myeloid Cells / metabolism
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Protein Biosynthesis
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-myb / metabolism
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Stability / genetics
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Trans-Activators / metabolism
  • Transcriptome / genetics
  • Up-Regulation / genetics

Substances

  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myb
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Trans-Activators
  • proto-oncogene protein Spi-1
  • N-methyladenosine
  • METTL14 protein, human
  • Methyltransferases
  • Mettl14 protein, mouse
  • Adenosine