英国惠康基因组研究园George S. Vassiliou和Moritz Gerstung研究团队合作取得一项新成果。经过不懈努力，他们揭示出克隆造血的纵向动力学和自然史。相关论文于2022年6月1日发表在《自然》杂志上。

研究人员追踪了385名55岁或以上个体存在的697种克隆性造血克隆，人群年龄变化的中位数为13年。研究发现，92.4%的克隆以稳定的指数速率扩增，不同的突变诱导了显著不同的增长率，从每年5%（DNMT3A和TP53）到超过50%（SRSF2P95H）不等。具有相同突变的克隆增长率每年相差约±5%，对慢性诱导因素的影响更大。

通过将该时间序列数据与来自年龄较大7个人的1,731个造血菌落全基因组序列的发育分析数据相结合，研究人员揭示了终生克隆行为的不同模式。在寡克隆环境竞争日益激烈的背景下，DNMT3A突变克隆优先在生命早期扩张，并在老年时表现出较慢的增长。相比之下，剪接基因突变只在生命晚期推动扩张，而TET2突变克隆出现在所有年龄段。最后，该研究发现产生更快克隆生长的突变具有更高的恶性进展风险。该研究揭示了克隆性造血的终生自然史，并对理解体细胞突变、衰老和克隆选择之间的相互作用提供了基本的见解。

据了解，随着年龄的增长，在人体组织中普遍出现由体细胞突变引起的克隆扩张，而在造血系统中，这种现象被称为克隆造血。对克隆性造血如何产生以及何时发展、控制其行为的因素、它如何与衰老相互作用以及这些变量如何与恶性进展相关的研究有限。

附：英文原文

Title: The longitudinal dynamics and natural history of clonal haematopoiesis

Author: Fabre, Margarete A., de Almeida, Jos Guilherme, Fiorillo, Edoardo, Mitchell, Emily, Damaskou, Aristi, Rak, Justyna, Orr, Valeria, Marongiu, Michele, Chapman, Michael Spencer, Vijayabaskar, M. S., Baxter, Joanna, Hardy, Claire, Abascal, Federico, Williams, Nicholas, Nangalia, Jyoti, Martincorena, Iigo, Campbell, Peter J., McKinney, Eoin F., Cucca, Francesco, Gerstung, Moritz, Vassiliou, George S.

Issue&Volume: 2022-06-01

Abstract: Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1,2,3,4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

DOI: 10.1038/s41586-022-04785-z

Source: https://www.nature.com/articles/s41586-022-04785-z