美国希望之城贝克曼研究所邓晓岚、陈建军、苏瑞和中国医科大学药学院魏敏杰研究组合作发现METTL16通过重编程BCAA代谢来驱动白血病发生和白血病干细胞(LSCs)自我更新。该项研究成果发表在2023年1月5日出版的《细胞—干细胞》上。

他们通过CRISPR-Cas9筛选和实验验证，表明METTL16是急性髓系白血病(AML)细胞生存的一个非常重要的基因。METTL16在人类AML细胞中异常过表达，特别是在LSC和白血病起始细胞(LICs)中。METTL16基因缺失显著抑制AML起始/发展和维持，显著减弱LSC/LIC自我更新，同时适度影响小鼠正常造血。在机制上，METTL16通过促进支链氨基酸(BCAA)转氨酶1 (BCAT1)和BCAT2以N6-甲基腺苷(m6A)依赖的方式在AML中表达和重编程BCAA代谢发挥致癌作用。总的来说，他们的研究结果描述了METTL16/m6A/BCAT1-2/BCAA轴在白血病发生中的作用，并强调了METTL16介导的m6A外延转录组和BCAA代谢重编程在白血病发生和LSC/LIC维持中的重要作用。

据悉，m6A是哺乳动物mRNAs中最常见的内部修饰，参与许多病理过程。METTL16是最近发现的m6A甲基转移酶。然而，它在白血病中的作用还有待研究。

附：英文原文

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

Author: 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

Issue&Volume: 2023/01/05

Abstract: N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, is involved in manypathological 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 myeloidleukemia (AML) cells via CRISPR-Cas9 screening and experimental validation. METTL16is 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 significantlyattenuates LSC/LIC self-renewal, while moderately influencing normal hematopoiesisin mice. Mechanistically, METTL16 exerts its oncogenic role by promoting expressionof branched-chain amino acid (BCAA) transaminase 1 (BCAT1) and BCAT2 in an m6A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our resultscharacterize 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/LICmaintenance.

DOI: 10.1016/j.stem.2022.12.006

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(22)00490-8