Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA.
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45219, USA; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning 110122, China.
Cell Stem Cell. 2018 Feb 1;22(2):191-205.e9. doi: 10.1016/j.stem.2017.11.016. Epub 2017 Dec 28.
N-methyladenosine (mA), the most prevalent internal modification in eukaryotic messenger RNAs (mRNAs), plays critical roles in many bioprocesses. However, its functions in normal and malignant hematopoiesis remain elusive. Here, we report that METTL14, a key component of the mA methyltransferase complex, is highly expressed in normal hematopoietic stem/progenitor cells (HSPCs) and acute myeloid leukemia (AML) cells carrying t(11q23), t(15;17), or t(8;21) and is downregulated during myeloid differentiation. Silencing of METTL14 promotes terminal myeloid differentiation of normal HSPCs and AML cells and inhibits AML cell survival/proliferation. METTL14 is required for development and maintenance of AML and self-renewal of leukemia stem/initiation cells (LSCs/LICs). Mechanistically, METTL14 exerts its oncogenic role by regulating its mRNA targets (e.g., MYB and MYC) through mA modification, while the protein itself is negatively regulated by SPI1. Collectively, our results reveal the SPI1-METTL14-MYB/MYC signaling axis in myelopoiesis and leukemogenesis and highlight the critical roles of METTL14 and mA modification in normal and malignant hematopoiesis.
N6-甲基腺苷（m6A）是真核信使 RNA（mRNA）中最普遍的内部修饰，在许多生物过程中发挥着关键作用。然而，其在正常和恶性造血中的功能仍不清楚。在这里，我们报告说，m6A 甲基转移酶复合物的关键组成部分 METTL14 在正常造血干/祖细胞（HSPCs）和携带 t（11q23）、t（15;17）或 t（8;21）的急性髓系白血病（AML）细胞中高度表达，并在髓系分化过程中下调。METTL14 的沉默促进了正常 HSPCs 和 AML 细胞的终末髓系分化，并抑制了 AML 细胞的存活/增殖。METTL14 是 AML 的发展和维持以及白血病干细胞/起始细胞（LSCs/LICs）的自我更新所必需的。在机制上，METTL14 通过 m6A 修饰调节其 mRNA 靶标（如 MYB 和 MYC）发挥致癌作用，而其自身蛋白则受到 SPI1 的负调控。总之，我们的研究结果揭示了骨髓生成和白血病发生中的 SPI1-METTL14-MYB/MYC 信号轴，并强调了 METTL14 和 m6A 修饰在正常和恶性造血中的关键作用。
