英国爱丁堡大学Tamir Chandra等研究人员合作发现，克隆造血的纵向动力学确定特定基因的适应性效应。该项研究成果于2022年7月4日在线发表在《自然—医学》杂志上。

研究人员表示，不确定潜能的克隆性造血（CHIP）在60岁以后的流行率迅速增加，并与恶性肿瘤、心脏病和缺血性中风的风险增加有关。CHIP是由造血干细胞和祖细胞（HSPC）的体细胞突变所驱动。

由于HSPC的突变经常驱动白血病，研究人员假设HSPC的适应性对从CHIP到白血病的转变有很大贡献。HSPC的适应性被定义为相对于不携带或只携带中性突变的细胞的增殖优势。如果不同基因的突变导致了不同的适应性优势，这可以使病人分层。研究人员利用纵向测序对老年12年的突变的适应性效应进行了量化，并开发了一种过滤方法，将个体突变背景与突变共同发生一起考虑，从而量化个体内变体的生长潜力。研究人员发现，基因特异性的适应性差异可以超过个体间的差异，因此，可以构成个性化临床管理的基础。

附：英文原文

Title: Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects

Author: Robertson, Neil A., Latorre-Crespo, Eric, Terradas-Terradas, Maria, Lemos-Portela, Jorge, Purcell, Alison C., Livesey, Benjamin J., Hillary, Robert F., Murphy, Lee, Fawkes, Angie, MacGillivray, Louise, Copland, Mhairi, Marioni, Riccardo E., Marsh, Joseph A., Harris, Sarah E., Cox, Simon R., Deary, Ian J., Schumacher, Linus J., Kirschner, Kristina, Chandra, Tamir

Issue&Volume: 2022-07-04

Abstract: Clonal hematopoiesis of indeterminate potential (CHIP) increases rapidly in prevalence beyond age 60 and has been associated with increased risk for malignancy, heart disease and ischemic stroke. CHIP is driven by somatic mutations in hematopoietic stem and progenitor cells (HSPCs). Because mutations in HSPCs often drive leukemia, we hypothesized that HSPC fitness substantially contributes to transformation from CHIP to leukemia. HSPC fitness is defined as the proliferative advantage over cells carrying no or only neutral mutations. If mutations in different genes lead to distinct fitness advantages, this could enable patient stratification. We quantified the fitness effects of mutations over 12years in older age using longitudinal sequencing and developed a filtering method that considers individual mutational context alongside mutation co-occurrence to quantify the growth potential of variants within individuals. We found that gene-specific fitness differences can outweigh inter-individual variation and, therefore, could form the basis for personalized clinical management.

DOI: 10.1038/s41591-022-01883-3

Source: https://www.nature.com/articles/s41591-022-01883-3