MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK; Laboratory of Haematopoietic Stem Cell & Leukaemia Biology, Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh EH16 4UU, UK; Institute for Stem Cell Research, School of Biological Sciences, University of Edinburgh, Edinburgh EH16 4UU, UK; Wellcome Centre for Cell Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3BF, UK.
Cell Stem Cell. 2019 Jul 3;25(1):137-148.e6. doi: 10.1016/j.stem.2019.03.021. Epub 2019 Apr 25.
Acute myeloid leukemia (AML) is an aggressive clonal disorder of hematopoietic stem cells (HSCs) and primitive progenitors that blocks their myeloid differentiation, generating self-renewing leukemic stem cells (LSCs). Here, we show that the mRNA mA reader YTHDF2 is overexpressed in a broad spectrum of human AML and is required for disease initiation as well as propagation in mouse and human AML. YTHDF2 decreases the half-life of diverse mA transcripts that contribute to the overall integrity of LSC function, including the tumor necrosis factor receptor Tnfrsf2, whose upregulation in Ythdf2-deficient LSCs primes cells for apoptosis. Intriguingly, YTHDF2 is not essential for normal HSC function, with YTHDF2 deficiency actually enhancing HSC activity. Thus, we identify YTHDF2 as a unique therapeutic target whose inhibition selectively targets LSCs while promoting HSC expansion.
急性髓系白血病（AML）是一种造血干细胞（HSCs）和原始祖细胞的侵袭性克隆疾病，它阻止其髓样分化，产生自我更新的白血病干细胞（LSCs）。在这里，我们表明，mRNA mA 阅读器 YTHDF2 在广泛的人类 AML 中过表达，并且需要其起始以及在小鼠和人类 AML 中的增殖。YTHDF2 降低了多种 mA 转录本的半衰期，这些转录本有助于 LSC 功能的整体完整性，包括肿瘤坏死因子受体 TNFRSF2，其在 Ythdf2 缺陷型 LSCs 中的上调使细胞对细胞凋亡敏感。有趣的是，YTHDF2 对于正常 HSC 功能不是必需的，YTHDF2 缺乏实际上增强了 HSC 的活性。因此，我们将 YTHDF2 鉴定为一个独特的治疗靶点，其抑制可选择性地靶向 LSCs，同时促进 HSC 扩增。
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