急性髓性白血病的发展需要对 RNA m6A 修饰进行重编程。

Weidong Liu, Yuhua Wang, Shuxin Yao, Guoqiang Han, Jin Hu, Rong Yin, Fuling Zhou, Ying Cheng, Haojian Zhang
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引用次数: 0

摘要

造血稳态由造血干细胞(HSCs)维持,它受到多层次的严格控制,以维持造血干细胞的自我更新能力和分化潜能。造血干细胞自我更新和分化失调会导致血液病的发生,包括急性髓性白血病(AML)。因此,了解造血干细胞维持和血液恶性肿瘤发展的内在机制是干细胞生物学的基础科学研究之一。N 6-甲基腺苷(m6A)是哺乳动物信使核糖核酸(mRNA)中的一种常见修饰,在各种生物过程中发挥着重要作用。在这项研究中,我们对急性髓细胞性白血病中造血干细胞和祖细胞(HSPCs)以及白血病启动细胞(LICs)的RNA m6A甲基组的动态进行了比较分析。我们发现,RNA m6A修饰调控长期造血干细胞向短期造血干细胞的转化,并决定造血干细胞的系承。有趣的是,m6A修饰会导致重编程,从而促进急性髓细胞性白血病发育过程中的细胞转化,而LIC特异性m6A靶点会被不同的m6A阅读器识别。此外,超长链脂肪酸转运体 ATP 结合盒 D 亚家族成员 2(ABCD2)是促进急性髓细胞性白血病发展的关键因素,缺失 ABCD2 会损害人类白血病细胞的克隆生成能力、抑制增殖并促进凋亡。这项研究全面了解了 m6A 在正常造血和白血病发生过程中调控细胞状态转变的作用,并发现 ABCD2 是急性髓细胞性白血病发生的关键因素。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reprogramming of RNA m6A Modification Is Required for Acute Myeloid Leukemia Development.

Hematopoietic homeostasis is maintained by hematopoietic stem cells (HSCs), and it is tightly controlled at multiple levels to sustain the self-renewal capacity and differentiation potential of HSCs. Dysregulation of self-renewal and differentiation of HSCs leads to the development of hematologic diseases, including acute myeloid leukemia (AML). Thus, understanding the underlying mechanisms of HSC maintenance and the development of hematologic malignancies is one of the fundamental scientific endeavors in stem cell biology. N  6-methyladenosine (m6A) is a common modification in mammalian messenger RNAs (mRNAs) and plays important roles in various biological processes. In this study, we performed a comparative analysis of the dynamics of the RNA m6A methylome of hematopoietic stem and progenitor cells (HSPCs) and leukemia-initiating cells (LICs) in AML. We found that RNA m6A modification regulates the transformation of long-term HSCs into short-term HSCs and determines the lineage commitment of HSCs. Interestingly, m6A modification leads to reprogramming that promotes cellular transformation during AML development, and LIC-specific m6A targets are recognized by different m6A readers. Moreover, the very long chain fatty acid transporter ATP-binding cassette subfamily D member 2 (ABCD2) is a key factor that promotes AML development, and deletion of ABCD2 damages clonogenic ability, inhibits proliferation, and promotes apoptosis of human leukemia cells. This study provides a comprehensive understanding of the role of m6A in regulating cell state transition in normal hematopoiesis and leukemogenesis, and identifies ABCD2 as a key factor in AML development.

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