白血病中的致癌增强子

IF 11.5 Q1 HEMATOLOGY
Roger Mulet-Lazaro, Ruud Delwel
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引用次数: 0

摘要

尽管白血病发生的研究传统上侧重于蛋白编码基因,但增强子失调的作用正日益得到认可。高通量测序技术的出现以及对增强子生物学的深入了解,揭示了各种遗传和表观遗传病变是如何产生致癌增强子并推动转化的。这些畸变包括导致增强子劫持的易位、调节增强子活性的点突变以及改变增强子剂量的拷贝数改变。在这篇综述中,我们以白血病为背景描述了这些机制,并讨论了针对这些调控元件的潜在治疗途径。意义重大:大规模测序项目发现了白血病中的复发性基因突变,但情况仍不全面:一些患者没有此类畸变,而另一些患者只携带少数几个基因突变,这些基因突变本身不足以导致转化。增强子功能障碍是缺失的部分之一,它直到最近才成为白血病发生的关键驱动因素。因此,了解增强子失调的各种机制是全面了解白血病及其病因的关键,也是在精准医疗时代开发靶向疗法的关键。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Oncogenic Enhancers in Leukemia.

Although the study of leukemogenesis has traditionally focused on protein-coding genes, the role of enhancer dysregulation is becoming increasingly recognized. The advent of high-throughput sequencing, together with a better understanding of enhancer biology, has revealed how various genetic and epigenetic lesions produce oncogenic enhancers that drive transformation. These aberrations include translocations that lead to enhancer hijacking, point mutations that modulate enhancer activity, and copy number alterations that modify enhancer dosage. In this review, we describe these mechanisms in the context of leukemia and discuss potential therapeutic avenues to target these regulatory elements. Significance: Large-scale sequencing projects have uncovered recurrent gene mutations in leukemia, but the picture remains incomplete: some patients harbor no such aberrations, whereas others carry only a few that are insufficient to bring about transformation on their own. One of the missing pieces is enhancer dysfunction, which only recently has emerged as a critical driver of leukemogenesis. Knowledge of the various mechanisms of enhancer dysregulation is thus key for a complete understanding of leukemia and its causes, as well as the development of targeted therapies in the era of precision medicine.

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来源期刊
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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