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

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

Cell stem cell (2023-01-08)
Li Han, Lei Dong, Keith Leung, Zhicong Zhao, Yangchan Li, Lei Gao, Zhenhua Chen, Jianhuang Xue, Ying Qing, Wei Li, Sheela Pangeni Pokharel, Min Gao, Meiling Chen, Chao Shen, Brandon Tan, Andrew Small, Kitty Wang, Zheng Zhang, Xi Qin, Lu Yang, Mark Wunderlich, Bin Zhang, James C Mulloy, Guido Marcucci, Chun-Wei Chen, Minjie Wei, Rui Su, Jianjun Chen, Xiaolan Deng
ABSTRACT

N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m6A 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 m6A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/m6A/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated m6A epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.

MATERIALS
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Product Description

Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, clone M2, purified immunoglobulin (Purified IgG1 subclass), buffered aqueous solution (10 mM sodium phosphate, 150 mM NaCl, pH 7.4, containing 0.02% sodium azide)
Sigma-Aldrich
Puromycin dihydrochloride from Streptomyces alboniger, powder, BioReagent, suitable for cell culture
Sigma-Aldrich
Actinomycin D, from Streptomyces sp., suitable for cell culture, ≥95%
Sigma-Aldrich
Anti-METTL16 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution