Leukemia ( IF 12.8 ) Pub Date : 2024-09-09 , DOI: 10.1038/s41375-024-02406-4 Austin Boucher 1 , Josiah Murray 2 , Sridhar Rao 2, 3, 4
The cohesin complex, encoded by SMC3, SMC1A, RAD21, and STAG2, is a critical regulator of DNA-looping and gene expression. Over a decade has passed since recurrent mutations affecting cohesin subunits were first identified in myeloid malignancies such as Acute Myeloid Leukemia (AML). Since that time there has been tremendous progress in our understanding of chromatin structure and cohesin biology, but critical questions remain because of the multiple critical functions the cohesin complex is responsible for. Recent findings have been particularly noteworthy with the identification of crosstalk between DNA-looping and chromatin domains, a deeper understanding of how cohesin establishes sister chromatid cohesion, a renewed interest in cohesin’s role for DNA damage response, and work demonstrating cohesin’s importance for Polycomb repression. Despite these exciting findings, the role of cohesin in normal hematopoiesis, and the precise mechanisms by which cohesin mutations promote cancer, remain poorly understood. This review discusses what is known about the role of cohesin in normal hematopoiesis, and how recent findings could shed light on the mechanisms through which cohesin mutations promote leukemic transformation. Important unanswered questions in the field, such as whether cohesin plays a role in HSC heterogeneity, and the mechanisms by which it regulates gene expression at a molecular level, will also be discussed. Particular attention will be given to the potential therapeutic vulnerabilities of leukemic cells with cohesin subunit mutations.
中文翻译:
急性髓系白血病的黏连蛋白突变
由 SMC3、SMC1A、RAD21 和 STAG2 编码的黏连蛋白复合体是 DNA 环和基因表达的关键调节因子。自从在急性髓性白血病 (AML) 等髓系恶性肿瘤中首次发现影响黏连蛋白亚基的复发性突变以来,已经过去了十多年。从那时起,我们对染色质结构和黏聚蛋白生物学的理解取得了巨大进步,但由于黏连蛋白复合物负责多种关键功能,关键问题仍然存在。最近的发现特别值得注意,因为发现了 DNA 环结构域和染色质结构域之间的串扰,更深入地了解了黏连蛋白如何建立姐妹染色单体凝聚力,对黏连蛋白在 DNA 损伤反应中的作用重新产生了兴趣,以及证明了黏连蛋白对多梳抑制的重要性。尽管有这些令人兴奋的发现,但人们对黏连蛋白在正常造血中的作用以及黏连蛋白突变促进癌症的确切机制仍然知之甚少。本综述讨论了关于黏连蛋白在正常造血中的作用的已知情况,以及最近的发现如何阐明黏连蛋白突变促进白血病转化的机制。还将讨论该领域重要的未解问题,例如黏连蛋白是否在 HSC 异质性中发挥作用,以及它在分子水平上调节基因表达的机制。将特别关注具有黏连蛋白亚基突变的白血病细胞的潜在治疗脆弱性。