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

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.