小柯机器人

美国斯坦福大学医学院Siddhartha Jaiswal等研究人员合作发现，TCL1A的异常激活促进克隆性造血的干细胞扩张。相关论文于2023年4月12日在线发表于国际学术期刊《自然》。

研究人员表示，一组不同的驱动基因的突变增加了造血干细胞（HSC）的生存能力，导致克隆性造血。这些病变是血癌的前兆，但其适应性优势的基础在很大程度上仍然是未知的，部分原因是缺乏大型队列，其中克隆扩展率已被纵向采样评估。

为了规避这一限制，研究人员开发了一种方法，从单一时间点的数据中推断出扩张率。研究人员将这种方法应用于5071名有克隆造血功能的人。一项全基因组关联研究显示，TCL1A启动子中的一个常见的遗传性多态性与克隆性造血的扩张速度总体较慢有关，但这种影响因驱动基因而异。携带这种保护性等位基因的人，在TET2、ASXL1、SF3B1和SRSF2驱动基因突变的克隆中表现出明显的生长速度或流行率下降，但在DNMT3A驱动基因突变的克隆中没有看到这种影响。TCL1A在正常或DNMT3A突变的造血干细胞中没有表达，但引入TET2或ASXL1的突变导致TCL1A蛋白的表达和造血干细胞在体外的扩增。

保护性等位基因限制了TCL1A的表达和突变造血干细胞的扩增，实验性敲除TCL1A表达也是如此。强制表达TCL1A促进了人类造血干细胞在体外和小鼠造血干细胞在体内的扩增。这些结果表明，几个常见的突变驱动基因在克隆造血中的适应性优势可能是由TCL1A的激活介导的。

附：英文原文

Title: Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis

Author: Weinstock, Joshua S., Gopakumar, Jayakrishnan, Burugula, Bala Bharathi, Uddin, Md Mesbah, Jahn, Nikolaus, Belk, Julia A., Bouzid, Hind, Daniel, Bence, Miao, Zhuang, Ly, Nghi, Mack, Taralynn M., Luna, Sofia E., Prothro, Katherine P., Mitchell, Shaneice R., Laurie, Cecelia A., Broome, Jai G., Taylor, Kent D., Guo, Xiuqing, Sinner, Moritz F., von Falkenhausen, Aenne S., Kb, Stefan, Shuldiner, Alan R., OConnell, Jeffrey R., Lewis, Joshua P., Boerwinkle, Eric, Barnes, Kathleen C., Chami, Nathalie, Kenny, Eimear E., Loos, Ruth J. F., Fornage, Myriam, Hou, Lifang, Lloyd-Jones, Donald M., Redline, Susan, Cade, Brian E., Psaty, Bruce M., Bis, Joshua C., Brody, Jennifer A., Silverman, Edwin K., Yun, Jeong H., Qiao, Dandi, Palmer, Nicholette D., Freedman, Barry I., Bowden, Donald W., Cho, Michael H., DeMeo, Dawn L., Vasan, Ramachandran S., Yanek, Lisa R., Becker, Lewis C., Kardia, Sharon L. R., Peyser, Patricia A., He, Jiang, Rienstra, Michiel, Van der Harst, Pim, Kaplan, Robert, Heckbert, Susan R., Smith, Nicholas L.

Issue&Volume: 2023-04-12

Abstract: Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2,3,4,5,6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, but this effect was not seen in clones with driver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimental knockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.

DOI: 10.1038/s41586-023-05806-1

Source: https://www.nature.com/articles/s41586-023-05806-1

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