The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression.

N6-methyladenosine (m6A), the most abundant modification in mRNAs, has been defined as a crucial modulator in the progression of acute myelogenous leukemia (AML). Identification of the key regulators of m6A modifications in AML could provide further insights into AML biology and uncover more effective therapeutic strategies for patients with AML. Here, we report overexpression of YTHDF1, an m6A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Whereas YTHDF1 was dispensable for normal hematopoiesis in mice, depletion of YTHDF1 attenuated self-renewal, proliferation, and leukemic capacity of primary human and mouse AML cells in vitro and in vivo. Mechanistically, YTHDF1 promoted the translation of cyclin E2 in an m6A-dependent manner. Structure-based virtual screening of FDA-approved drugs identified tegaserod as a potential YTHDF1 inhibitor. Tegaserod blocked the direct binding of YTHDF1 with m6A-modified mRNAs and inhibited YTHDF1-regulated cyclin E2 translation. Moreover, tegaserod reduced the viability of patient-derived AML cells in vitro and prolonged survival in patient-derived xenograft models. Together, our study defines YTHDF1 as an integral regulator of AML progression by regulating the expression of m6A-modified mRNAs, which might serve as a potential therapeutic target for AML. The m6A reader YTHDF1 is required for progression of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth. ©2023 American Association for Cancer Research.

Citation

Yun-Guang Hong, Zhigang Yang, Yan Chen, Tian Liu, Yuyuan Zheng, Chun Zhou, Guo-Cai Wu, Yinhui Chen, Juan Xia, Ruiting Wen, Wenxin Liu, Yi Zhao, Jin Chen, Xiangwei Gao, Zhanghui Chen. The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression. Cancer research. 2023 Mar 15;83(6):845-860

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PMID: 36634204

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