| Literature DB >> 29290617 |
Hengyou Weng1, Huilin Huang1, Huizhe Wu2, Xi Qin1, Boxuan Simen Zhao3, Lei Dong1, Hailing Shi3, Jennifer Skibbe1, Chao Shen1, Chao Hu4, Yue Sheng5, Yungui Wang4, Mark Wunderlich6, Bin Zhang7, Louis C Dore3, Rui Su1, Xiaolan Deng2, Kyle Ferchen1, Chenying Li4, Miao Sun8, Zhike Lu3, Xi Jiang1, Guido Marcucci7, James C Mulloy6, Jianhua Yang9, Zhijian Qian5, Minjie Wei10, Chuan He11, Jianjun Chen12.
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.Entities:
Keywords: HSC; HSPCs; LSCs/LICs; METTL14; MYB; MYC; N(6)-methyladenosine modification; SPI1; acute myeloid leukemia; myeloid differentiation block
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Year: 2017 PMID： 29290617 PMCID： PMC5860916 DOI： 10.1016/j.stem.2017.11.016
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 25.269