Therapeutic Opportunities of Targeting Canonical and Noncanonical PcG/TrxG Functions in Acute Myeloid Leukemia.

IF 7.7 2区生物学 Q1 GENETICS & HEREDITY

Annual review of genomics and human genetics Pub Date : 2021-08-31 Epub Date: 2021-04-30 DOI:10.1146/annurev-genom-111120-102443

Bernd B Zeisig, Chi Wai Eric So

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Abstract

Transcriptional deregulation is a key driver of acute myeloid leukemia (AML), a heterogeneous blood cancer with poor survival rates. Polycomb group (PcG) and Trithorax group (TrxG) genes, originally identified in Drosophila melanogaster several decades ago as master regulators of cellular identity and epigenetic memory, not only are important in mammalian development but also play a key role in AML disease biology. In addition to their classical canonical antagonistic transcriptional functions, noncanonical synergistic and nontranscriptional functions of PcG and TrxG are emerging. Here, we review the biochemical properties of major mammalian PcG and TrxG complexes and their roles in AML disease biology, including disease maintenance as well as drug resistance. We summarize current efforts on targeting PcG and TrxG for treatment of AML and propose rational synthetic lethality and drug-induced antagonistic pleiotropy options involving PcG and TrxG as potential new therapeutic avenues for treatment of AML.

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针对急性髓性白血病中规范和非规范 PcG/TrxG 功能的治疗机会

转录失调是急性髓性白血病（AML）的主要诱因，AML是一种异质性血液癌症，存活率很低。多聚核糖体组（PcG）和Trithorax组（TrxG）基因最初是几十年前在黑腹果蝇中发现的，它们是细胞特性和表观遗传记忆的主调控因子，不仅在哺乳动物的发育过程中非常重要，而且在急性髓性白血病的生物学中也发挥着关键作用。除了经典的拮抗转录功能外，PcG 和 TrxG 的非经典协同和非转录功能也在不断涌现。在此，我们回顾了哺乳动物主要 PcG 和 TrxG 复合物的生化特性及其在急性髓细胞性疾病生物学中的作用，包括疾病维持和耐药性。我们总结了目前针对 PcG 和 TrxG 治疗急性髓细胞性白血病所做的努力，并提出了涉及 PcG 和 TrxG 的合理合成致死率和药物诱导拮抗多态性方案，作为治疗急性髓细胞性白血病的潜在新疗法途径。

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来源期刊

Annual review of genomics and human genetics 生物-遗传学

CiteScore

14.90

自引率

1.10%

发文量

期刊介绍： Since its inception in 2000, the Annual Review of Genomics and Human Genetics has been dedicated to showcasing significant developments in genomics as they pertain to human genetics and the human genome. The journal emphasizes genomic technology, genome structure and function, genetic modification, human variation and population genetics, human evolution, and various aspects of human genetic diseases, including individualized medicine.