Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
Cell Stem Cell. 2023 Jan 5;30(1):52-68.e13. doi: 10.1016/j.stem.2022.12.006.
N-methyladenosine (mA), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified mA 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 mA-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/mA/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated mA epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.
N6-甲基腺苷（m6A）是哺乳动物 mRNA 中最普遍的内部修饰物，参与许多病理过程。METTL16 是最近发现的 mA 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 筛选和实验验证表明，METTL16 是急性髓系白血病（AML）细胞存活的高度必需基因。METTL16 在人 AML 细胞中异常过表达，特别是在白血病干细胞（LSCs）和白血病起始细胞（LICs）中。METTL16 的基因缺失显著抑制 AML 的起始/发展和维持，并显著减弱 LSC/LIC 的自我更新，而在小鼠中适度影响正常造血。在机制上，METTL16 通过以 mA 依赖的方式促进支链氨基酸（BCAA）转氨酶 1（BCAT1）和 BCAT2 的表达，并在 AML 中重新编程 BCAA 代谢来发挥致癌作用。总之，我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 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。
