AI Article Synopsis
- N-methyladenosine (mA) is a key modification in mammalian mRNAs and is linked to various diseases, including leukemia.
- Researchers identified METTL16 as a crucial gene for the survival of acute myeloid leukemia (AML) cells, finding it is overexpressed in human AML and especially prevalent in leukemia stem cells.
- The study reveals that depleting METTL16 hampers AML development and stem cell self-renewal, largely by altering the metabolism of branched-chain amino acids (BCAAs) through the regulation of enzymes BCAT1 and BCAT2, positioning METTL16 as a significant player in leukemia progression.
Article Abstract
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.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9838187 | PMC |
| http://dx.doi.org/10.1016/j.stem.2022.12.006 | DOI Listing |
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