METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism

N -methyladenosine (m A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m A methyltransferase. However, its role in leukemia has yet to be investigated. Here, we show that METTL16 is a highly essential gene f...

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Published inCell stem cell Vol. 30; no. 1; pp. 52 - 68.e13
Main Authors Han, Li, Dong, Lei, Leung, Keith, Zhao, Zhicong, Li, Yangchan, Gao, Lei, Chen, Zhenhua, Xue, Jianhuang, Qing, Ying, Li, Wei, Pokharel, Sheela Pangeni, Gao, Min, Chen, Meiling, Shen, Chao, Tan, Brandon, Small, Andrew, Wang, Kitty, Zhang, Zheng, Qin, Xi, Yang, Lu, Wunderlich, Mark, Zhang, Bin, Mulloy, James C, Marcucci, Guido, Chen, Chun-Wei, Wei, Minjie, Su, Rui, Chen, Jianjun, Deng, Xiaolan
Format Journal Article
LanguageEnglish
Published United States 05.01.2023
Subjects
Amino Acids, Branched-Chain - genetics
Amino Acids, Branched-Chain - metabolism
Animals
Carcinogenesis - pathology
Cell Self Renewal
Humans
Leukemia, Myeloid, Acute - pathology
Mammals - metabolism
Methyltransferases - genetics
Methyltransferases - metabolism
Mice
Neoplastic Stem Cells - pathology
RNA, Messenger - metabolism
Transaminases - genetics
Transaminases - metabolism
AML
leukemia-initiating cells
m6A modification
leukemia stem cells
BCAT1
METTL16
self-renewal
BCAA metabolism
LSCs/LICs
BCAT2
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Summary:N -methyladenosine (m A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m A methyltransferase. However, its role in leukemia has yet to be investigated. Here, we show that METTL16 is a highly essential gene for the survival of acute myeloid leukemia (AML) cells via CRISPR-Cas9 screening and experimental validation. METTL16 is aberrantly overexpressed in human AML cells, especially in leukemia stem cells (LSCs) and leukemia-initiating cells (LICs). Genetic depletion of METTL16 dramatically suppresses AML initiation/development and maintenance and significantly attenuates LSC/LIC self-renewal, while moderately influencing normal hematopoiesis in mice. Mechanistically, METTL16 exerts its oncogenic role by promoting expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) and BCAT2 in an m A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/m A/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated m A epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.
Bibliography:AUTHOR CONTRIBUTIONS
L.H., R. S., J.C. and X.D. conceived and designed the project, and supervised the research; L.H., K.L., Z.Zhao, Y.L., L.G., Z.C., Y.Q., W.L., M.G., M. C., C.S., B.T., A.S., K.W., Z.Zheng, X.Q., and X.D. performed experiments and/or data analysis; L.D. performed all the bioinformatics analysis; S.P.P., L.Y., and C.C. performed CRISPR screening; J.X. performed QQQ-MS; L.H., M. W., B.Z., J.C.M., G.M., M.W., R.S., J.C. and X.D. contributed reagents/analytic tools, patient samples, discussion, and grant support; L.H., M.W., R.S., J.C. and X.D. wrote the paper. All authors discussed the results and commented on the manuscript.
These authors contributed equally to this paper.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2022.12.006