急性髓系白血病（AML）的表观遗传变化：失调的功能引领新疗法
Epigenetic alterations in AML: Deregulated functions leading to new therapeutic options
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发表日期:2024
作者:
Kourosh Hayatigolkhatmi, Riccardo Valzelli, Oualid El Menna, Saverio Minucci
DOI:
10.1016/bs.ircmb.2024.06.003
摘要
急性髓系白血病（AML）导致造血分化过程的破坏。近年来取得了关键性进展，并开发出新的治疗策略。然而，诱导化疗仍是大多数AML患者的主要治疗手段。表观遗传失调在AML发病机制中起核心作用，支持白血病发生和白血病干细胞的维持。本文综述了DNA甲基化、组蛋白修饰和染色质重塑等改变的复杂相互作用在AML发展中的作用。我们探讨了DNA甲基转移酶（DNMTs）、组蛋白甲基转移酶（HMTs）、去甲基酶（KDMs）和HDACs等表观遗传调控因子在推动白血病细胞转化中的作用。此外，本文还讨论了染色体畸变对表观基因组重塑的影响以及靶向表观遗传脆弱性的潜力作为治疗策略。理解AML的表观遗传景观，为新型治疗途径提供了启示，包括表观遗传调节剂及其联合疗法，以改善治疗效果并克服药物抗性。
Abstract
Acute myeloid leukemia (AML) results in disruption of the hematopoietic differentiation process. Crucial progress has been made, and new therapeutic strategies for AML have been developed. Induction chemotherapy, however, remains the main option for the majority of AML patients. Epigenetic dysregulation plays a central role in AML pathogenesis, supporting leukemogenesis and maintenance of leukemic stem cells. Here, we provide an overview of the intricate interplay of altered epigenetic mechanisms, including DNA methylation, histone modifications, and chromatin remodeling, in AML development. We explore the role of epigenetic regulators, such as DNMTs, HMTs, KDMs, and HDACs, in mediating gene expression patterns pushing towards leukemic cell transformation. Additionally, we discuss the impact of cytogenetic lesions on epigenomic remodeling and the potential of targeting epigenetic vulnerabilities as a therapeutic strategy. Understanding the epigenetic landscape of AML offers insights into novel therapeutic avenues, including epigenetic modifiers and particularly their use in combination therapies, to improve treatment outcomes and overcome drug resistance.