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

被引：871

作者：

Weng, Hengyou ^{[1
,12
]}

Huang, Huilin ^{[1
,12
]}

Wu, Huizhe ^{[1
,2
,12
]}

Qin, Xi ^{[1
,12
]}

Zhao, Boxuan Simen ^{[3
]}

Dong, Lei ^{[1
,12
]}

Shi, Hailing ^{[3
]}

Skibbe, Jennifer ^{[1
]}

Shen, Chao ^{[1
,12
]}

Hu, Chao ^{[1
,4
]}

Sheng, Yue ^{[5
,6
]}

Wang, Yungui ^{[1
,4
]}

Wunderlich, Mark ^{[7
]}

Zhang, Bin ^{[8
,9
]}

Dore, Louis C. ^{[3
]}

Su, Rui ^{[1
,12
]}

Deng, Xiaolan ^{[1
,2
,12
]}

Ferchen, Kyle ^{[1
]}

Li, Chenying ^{[1
,4
,12
]}

Sun, Miao ^{[10
]}

Lu, Zhike ^{[3
]}

Jiang, Xi ^{[1
,12
]}

Marcucci, Guido ^{[8
,9
]}

Mulloy, James C. ^{[7
]}

Yang, Jianhua ^{[11
]}

Qian, Zhijian ^{[5
,6
]}

Wei, Minjie ^{[2
]}

He, Chuan ^{[3
]}

Chen, Jianjun ^{[1
,12
]}

机构：

[1] Univ Cincinnati, Dept Canc Biol, Cincinnati, OH 45219 USA

[2] China Med Univ, Sch Pharm, Dept Pharmacol, Shenyang 110122, Liaoning, Peoples R China

[3] Univ Chicago, Howard Hughes Med Inst, Inst Biophys Dynam, Dept Chem,Dept Biochem & Mol Biol, 5841 S Maryland Ave, Chicago, IL 60637 USA

[4] Zhejiang Univ, Dept Hematol, Affiliated Hosp 1, Hangzhou 310003, Zhejiang, Peoples R China

[5] Univ Illinois, Dept Med, Chicago, IL 60612 USA

[6] Univ Illinois, Canc Res Ctr, Chicago, IL 60612 USA

[7] Cincinnati Childrens Hosp Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA

[8] City Hope Natl Med Ctr, Dept Hematol Malignancies Translat Sci, Duarte, CA 91010 USA

[9] City Hope Natl Med Ctr, Gehr Family Leukemia Ctr, Duarte, CA 91010 USA

[10] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA

[11] Sun Yat Sen Univ, Key Lab Gene Engn, Minist Educ, Guangzhou 510275, Guangdong, Peoples R China

[12] City Hope Natl Med Ctr, Dept Syst Biol, Beckman Res Inst, Monrovia, CA 91016 USA

来源：

CELL STEM CELL | 2018年 / 22卷 / 02期

关键词：

MYELOID-LEUKEMIA; TRANSCRIPTION FACTORS; NUCLEAR-RNA; METHYLATION; N6-METHYLADENOSINE; TRANSLATION; ENRICHMENT; MUTATION; DATABASE; SUBUNIT;

D O I：

10.1016/j.stem.2017.11.016

中图分类号：

Q813 [细胞工程];

学科分类号：

摘要：

N-6-methyladenosine (m(6)A), 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 m(6)A 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 m(6)A 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 m(6)A modification in normal and malignant hematopoiesis.

引用

页码：191 / +

页数：24

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