小柯机器人

美国哈佛医学院Vijay G. Sankaran等研究人员合作揭示通过改变的转录延伸产生的遗传血癌倾向。该项研究成果于2024年1月12日在线发表在《细胞》杂志上。

研究人员在一个大型人群队列中进行了罕见变异关联研究，以确定这些血癌的遗传易感基因。CTR9编码PAF1转录延伸复合体的一个关键成分，是被发现的重要基因之一。在病例中发现的风险变异会导致功能缺失，并使罹患骨髓恶性肿瘤的几率增加10倍。CTR9部分功能缺失会增加超级延伸复合体介导的转录活性，从而增加造血干细胞自我更新关键调节因子的表达，进而扩增人类造血干细胞（HSC）。

通过跟进一项人类遗传学研究对骨髓恶性肿瘤遗传易感性的深入了解，研究人员确定了PAF1和超级延伸复合物之间一种之前未知的拮抗相互作用。这些见解可帮助人们采用有针对性的方法来预防血癌。

研究人员表示，尽管在确定导致骨髓恶性肿瘤的各种体细胞突变方面取得了进展，但这些癌症的重要遗传因素在很大程度上仍未得到解释。

附：英文原文

Title: Inherited blood cancer predisposition through altered transcription elongation

Author: Jiawei Zhao, Liam D. Cato, Uma P. Arora, Erik L. Bao, Samuel C. Bryant, Nicholas Williams, Yuemeng Jia, Seth R. Goldman, Jyoti Nangalia, Michael A. Erb, Seychelle M. Vos, Scott A. Armstrong, Vijay G. Sankaran

Issue&Volume: 2024-01-12

Abstract: Despite advances in defining diverse somatic mutations that cause myeloid malignancies, a significant heritable component for these cancers remains largely unexplained. Here, we perform rare variant association studies in a large population cohort to identify inherited predisposition genes for these blood cancers. CTR9, which encodes a key component of the PAF1 transcription elongation complex, is among the significant genes identified. The risk variants found in the cases cause loss of function and result in a ～10-fold increased odds of acquiring a myeloid malignancy. Partial CTR9 loss of function expands human hematopoietic stem cells (HSCs) by increased super elongation complex-mediated transcriptional activity, which thereby increases the expression of key regulators of HSC self-renewal. By following up on insights from a human genetic study examining inherited predisposition to the myeloid malignancies, we define a previously unknown antagonistic interaction between the PAF1 and super elongation complexes. These insights could enable targeted approaches for blood cancer prevention.

DOI: 10.1016/j.cell.2023.12.016

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01348-X