华盛顿大学医学院Kelly L. Bolton团队的一项最新研究发现CDK4/6抑制减轻化疗诱导的TP53突变克隆造血扩增。相关论文发表在2026年3月11日出版的《自然—遗传学》杂志上。

在他们的随机临床试验中，该课题组人员发现CDK4/6抑制剂trilaciclib与各种化疗方案和不同癌症患者群体联合使用，可以减轻DNA损伤反应基因（包括TP53）突变的CH克隆与化疗相关的扩增。这一发现也在TP53突变体CH的同基因母位模型中被观察到，表明CDK4/6抑制通过促进造血干细胞和祖细胞的静止，降低TP53突变体克隆的干性优势，从而阻止铂诱导的TP53竞争性再生。这代表了一个潜在的药理学策略的概念证明，以阻止化疗诱导的白血病前TP53突变克隆的扩张。

研究人员表示，治疗相关性髓系肿瘤（tMN）是在癌症治疗中暴露于细胞毒性治疗的致命后果。已有TP53克隆造血（CH）的个体是tMN的高危人群，避免治疗是降低tMN风险的唯一策略。

附：英文原文

Title: CDK4/6 inhibition mitigates chemotherapy-induced expansion of TP53-mutant clonal hematopoiesis

Author: Chan, Irenaeus C. C., Zhang, Pu, Pan, Xiangyu, Castro, Cynthia, Fox, Nina, Lewis, Alexander M., Weis, Kenyon, Cuibus, Adriana, Tittley, Steven, Petrone, Giulia, Beeler, J. Scott, Tran, Duc, Mustion, Griffen, Fronick, Catrina, Stopsack, Konrad H., Cruchaga, Carlos, Abdel-Wahab, Omar, Bolton, Kelly L.

Issue&Volume: 2026-03-11

Abstract: Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, in four randomized clinical trials, we show that the CDK4/6 inhibitor trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse populations of patients with cancer, mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response genes, including TP53. This finding was also observed in a syngeneic mouse model of TP53-mutant CH, demonstrating that CDK4/6 inhibition blocks platinum-induced TP53 competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing the stemness advantage of TP53-mutant clones. This represents a proof of concept for a potential pharmacologic strategy to block chemotherapy-induced expansion of preleukemic TP53-mutant clones.

DOI: 10.1038/s41588-026-02526-w

Source: https://www.nature.com/articles/s41588-026-02526-w