Published on Feb. 1, 2018 in Cell Stem Cell volume 22(2).

PubMed ID: 29290617

DOI: S1934-5909(17)30468-X

Abstract:

N(6)-methyladenosine (m(6)A), the most prevalent internal modification in eukaryoticmessenger RNAs (mRNAs), plays critical roles in many bioprocesses. However, itsfunctions in normal and malignant hematopoiesis remain elusive. Here, we report thatMETTL14, a key component of the m(6)A methyltransferase complex, is highly expressedin 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 duringmyeloid differentiation. Silencing of METTL14 promotes terminal myeloiddifferentiation of normal HSPCs and AML cells and inhibits AML cellsurvival/proliferation. METTL14 is required for development and maintenance of AMLand 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 m(6)A modification, while the protein itself is negatively regulated bySPI1. Collectively, our results reveal the SPI1-METTL14-MYB/MYC signaling axis inmyelopoiesis and leukemogenesis and highlight the critical roles of METTL14 andm(6)A modification in normal and malignant hematopoiesis.CI - Copyright © 2017 Elsevier Inc. All rights reserved.