Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
The Gehr Family Center for Leukemia Research, Beckman Research Institute of City of Hope, Monrovia, CA, USA.
Adv Exp Med Biol. 2019;1143:75-93. doi: 10.1007/978-981-13-7342-8_4.
As the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), N -methyladenosine (mA) modification has been shown recently to posttranscriptionally regulate expression of thousands of messenger RNA (mRNA) transcripts in each mammalian cell type in a dynamic and reversible manner. This epigenetic mark is deposited by the mA methyltransferase complex (i.e., the METTL3/METTL14/WTAP complex and other cofactor proteins) and erased by mA demethylases such as FTO and ALKBH5. Specific recognition of these mA-modified mRNAs by mA-binding proteins (i.e., mA readers) determines the fate of target mRNAs through affecting splicing, nuclear export, RNA stability, and/or translation. During the past few years, mA modification has been demonstrated to play a critical role in many major normal bioprocesses including self-renewal and differentiation of embryonic stem cells and hematopoietic stem cells, tissue development, circadian rhythm, heat shock or DNA damage response, and sex determination. Thus, it is not surprising that dysregulation of the mA machinery is also closely associated with pathogenesis and drug response of both solid tumors and hematologic malignancies. In this chapter, we summarize and discuss recent findings regarding the biological functions and underlying mechanisms of mA modification and the associated machinery in normal hematopoiesis and the initiation, progression, and drug response of acute myeloid leukemia (AML), a major subtype of leukemia usually associated with unfavorable prognosis.
作为真核生物信使 RNA（mRNA）中最丰富的内部修饰，N6-甲基腺苷（m6A）修饰最近被证明以动态和可逆的方式在后转录水平上调节每种哺乳动物细胞类型中数千个 mRNA 转录本的表达。这种表观遗传标记由 m6A 甲基转移酶复合物（即 METTL3/METTL14/WTAP 复合物和其他辅助因子蛋白）沉积，并由 m6A 去甲基酶如 FTO 和 ALKBH5 去除。这些 m6A 修饰的 mRNA 被 m6A 结合蛋白（即 m6A 阅读器）特异性识别，通过影响剪接、核输出、RNA 稳定性和/或翻译来决定靶 mRNA 的命运。在过去的几年中，m6A 修饰已被证明在许多主要的正常生物过程中发挥关键作用，包括胚胎干细胞和造血干细胞的自我更新和分化、组织发育、昼夜节律、热休克或 DNA 损伤反应以及性别决定。因此，m6A 机制的失调与实体瘤和血液恶性肿瘤的发病机制和药物反应密切相关也就不足为奇了。在本章中，我们总结和讨论了 m6A 修饰及其相关机制在正常造血以及急性髓系白血病（AML）的起始、进展和药物反应中的生物学功能和潜在机制的最新发现，AML 是一种通常与不良预后相关的主要白血病亚型。
