The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression
The RNA m6A Reader YTHDF1 Is Required for Acute Myeloid Leukemia Progression
复制标题
DOI：
10.1158/0008-5472.can-21-4249
复制
发表时间：
2023-03-15
期刊：
影响因子：
11.2
通讯作者：
Chen, Zhanghui
中科院分区：
文献类型：
--
作者：
Hong, Yun-Guang;Yang, Zhigang;Chen, Zhanghui
N-6-甲基腺苷 (m(6)A) 是 mRNA 中最丰富的修饰，已被定义为急性髓性白血病 (AML) 进展的关键调节剂。鉴定 AML 中 m(6)A 修饰的关键调节因子可以进一步了解 AML 生物学，并为 AML 患者发现更有效的治疗策略。在这里，我们报告了人类 AML 样本中 YTHDF1（一种 m(6)A 读取蛋白）在蛋白质水平上的过度表达，并在白血病干细胞 (LSC) 中富集。尽管 YTHDF1 对于小鼠的正常造血来说是可有可无的，但 YTHDF1 的耗竭会减弱人类和小鼠原代 AML 细胞在体外和体内的自我更新、增殖和白血病能力。从机制上讲，YTHDF1 以 m(6)A 依赖性方式促进细胞周期蛋白 E2 的翻译。对 FDA 批准的药物进行基于结构的虚拟筛选，将替加色罗确定为潜在的 YTHDF1 抑制剂。 Tegaserod 阻断 YTHDF1 与 m(6)A 修饰的 mRNA 的直接结合，并抑制 YTHDF1 调节的细胞周期蛋白 E2 翻译。此外，替加色罗降低了患者来源的 AML 细胞的体外活力，并延长了患者来源的异种移植模型的存活时间。总之，我们的研究通过调节 m(6)A 修饰的 mRNA 的表达，将 YTHDF1 定义为 AML 进展的整体调节因子，这可能作为 AML 的潜在治疗靶点。意义：m(6)A 阅读器 YTHDF1 是急性髓性白血病进展所必需的，并且可以用 FDA 批准的药物替加色罗作为靶点来抑制白血病生长。
N-6-methyladenosine (m(6)A), 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 m(6)A 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 m(6)A reader protein, in human AML samples at the protein level with enrichment in leukemia stem cells (LSC). Where-as 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 m(6)A-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 m(6)A-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 m(6)A-modified mRNAs, which might serve as a potential therapeutic target for AML.Significance: The m(6)A reader YTHDF1 is required for progres-sion of acute myelogenous leukemia and can be targeted with the FDA-approved drug tegaserod to suppress leukemia growth.