Acute myeloid leukemia with t(8;21) translocation: Molecular pathogenesis, potential therapeutics and future directions

IF 5.6 2区医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2025-01-27 DOI:10.1016/j.bcp.2025.116774

Pei Han Yu , Ze Yan Zhang , Yuan Yuan Kang , Ping Huang , Chang Yang , Hua Naranmandura

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Abstract

Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive blood cancer. Genetic abnormalities, such as the t(8;21) rearrangement, play a significant role in AML onset. This rearrangement leads to the formation of the RUNX1/RUNX1T1 fusion protein, disrupting gene regulation and genomic stability, ultimately causing full-blown leukemia. Despite a generally favorable prognosis, t(8;21) patients face relapse and chemotherapy resistance, particularly when harboring cooperating mutations. While advances in cellular genetics and molecular biology have improved AML treatment, there are currently no specific targeted therapies against RUNX1/RUNX1T1. Therefore, investigating targeted therapies for this AML subtype holds promise for patients. This review explores the complex landscape of t(8;21) AML, unravels the molecular mechanisms of RUNX1/RUNX1T1-driven leukemogenesis, and discusses recent advancements in target therapies including small molecule drugs and PROTAC. Our goal is to develop more effective and less toxic strategies for managing t(8;21) AML patients.

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急性髓系白血病伴t（8;21）易位：分子发病机制、潜在治疗方法及未来发展方向。

急性髓性白血病（AML）是一种高度异质性和侵袭性的血癌。遗传异常，如t（8;21）重排，在AML发病中起重要作用。这种重排导致RUNX1/RUNX1T1融合蛋白的形成，破坏基因调控和基因组稳定性，最终导致全面白血病。尽管预后普遍良好，但t（8;21）例患者面临复发和化疗耐药，特别是当携带合作突变时。虽然细胞遗传学和分子生物学的进步已经改善了AML的治疗，但目前还没有针对RUNX1/RUNX1T1的特异性靶向治疗。因此，研究针对这种AML亚型的靶向治疗为患者带来了希望。本文探讨了t(8;21) AML的复杂格局，揭示了RUNX1/ runx1t1驱动的白血病发生的分子机制，并讨论了包括小分子药物和PROTAC在内的靶向治疗的最新进展。我们的目标是开发更有效和毒性更小的策略来管理AML患者。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.