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<p>Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing <i>TP53</i> 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 <i>TP53</i>. This finding was also observed in a syngeneic mouse model of <i>TP53-</i>mutant CH, demonstrating that CDK4/6 inhibition blocks platinum-induced <i>TP53</i> competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing the stemness advantage of <i>TP53-</i>mutant clones. This represents a proof of concept for a potential pharmacologic strategy to block chemotherapy-induced expansion of preleukemic <i>TP53</i>-mutant clones.</p>

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

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月11日

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

摘要

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.