Department of Pharmacology and Therapeutics, University of Florida (UF) College of Medicine, Gainesville, Florida.
University of Florida Health Cancer Center, Gainesville, Florida.
Cancer Res. 2021 Jan 15;81(2):254-263. doi: 10.1158/0008-5472.CAN-20-3033. Epub 2020 Oct 21.
In the last decade, large-scale genomic studies in patients with hematologic malignancies identified recurrent somatic alterations in epigenetic modifier genes. Among these, the DNA methyltransferase has emerged as one of the most frequently mutated genes in adult myeloid as well as lymphoid malignancies and in clonal hematopoiesis. In this review, we discuss recent advances in our understanding of the biochemical and structural consequences of mutations on DNA methylation catalysis and binding interactions and summarize their effects on epigenetic patterns and gene expression changes implicated in the pathogenesis of hematologic malignancies. We then review the role played by mutant in clonal hematopoiesis, accompanied by its effect on immune cell function and inflammatory responses. Finally, we discuss how this knowledge informs therapeutic approaches for hematologic malignancies with mutant .
在过去的十年中,针对血液系统恶性肿瘤患者的大规模基因组研究鉴定出了表观遗传修饰基因中反复出现的体细胞改变。其中,DNA 甲基转移酶已成为成人髓系和淋巴系统恶性肿瘤以及克隆性造血中突变频率最高的基因之一。在这篇综述中,我们讨论了近年来对突变影响 DNA 甲基化催化和结合相互作用的生化和结构后果的理解进展,并总结了它们对涉及血液系统恶性肿瘤发病机制的表观遗传模式和基因表达变化的影响。然后,我们回顾了突变体在克隆性造血中所起的作用,以及其对免疫细胞功能和炎症反应的影响。最后,我们讨论了这些知识如何为突变体血液系统恶性肿瘤的治疗方法提供信息。