METTL16通过重新编程BCAA代谢驱动白血病发生和白血病干细胞的自我更新。
METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism.
发表日期：2023 Jan 05
作者：
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
来源：
Cell Stem Cell
摘要：
在哺乳动物mRNA中最普遍的内部修饰物N6-甲基腺苷（m6A）涉及许多病理过程。METTL16是一种最近被鉴定出的m6A甲基转移酶，然而其在白血病中的作用尚未被研究。在这里，我们通过CRISPR-Cas9筛选和实验验证显示METTL16是急性髓性白血病（AML）细胞生存所必不可少的基因。METTL16在人AML细胞中异常高表达，特别是在白血病干细胞（LSCs）和白血病引发细胞（LICs）中。METTL16的基因耗尽显著抑制AML起始／发展和维持，并且显著减弱LSC／LIC的自我更新，同时在小鼠中适度地影响正常造血。在机制上，METTL16通过在m6A依赖性方式中促进支链氨基酸（BCAA）转氨酶1（BCAT1）和BCAT2的表达并在AML中重编程BCAA代谢发挥其致癌作用。总体而言，我们的结果表征了leukemogenesis中的METTL16/m6A/BCAT1-2/BCAA轴并强调了METTL16介导的m6A表观转录组和BCAA代谢重编程在leukemogenesis和LSC／LIC维持中的关键作用。Copyright © 2022 Elsevier Inc. All rights reserved.
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.Copyright © 2022 Elsevier Inc. All rights reserved.