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

GSE285875 Mus musculus Expression profiling by high throughput sequencing 8 samples Submitted 2025/01/09 Platform GPL34290
Summary
Therapy-related myeloid neoplasms (tMN) represent 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 for development of tMN but currently avoidance of therapy is the only strategy to reduce tMN risk. Here, we show in four randomized clinical trials of the CDK4/6 inhibitor trilaciclib given in conjunction with a variety of chemotherapeutic regimens and across diverse cancer patient populations that trilaciclib mitigates expansion of chemotherapy-related CH clones with mutations in DNA damage response genes (including TP53, PPM1D, and CHEK2 mutations). This finding was also observed in a syngeneic murine model of TP53 mutant CH demonstrating that trilaciclib blocks platinum-induced TP53 competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing TP53 mutant stemness advantage. This represents the first demonstration of a pharmacologic strategy to block chemotherapy-induced expansion of pre-leukemic TP53-mutant clones.
Published in
CDK4/6 inhibition mitigates chemotherapy-induced expansion of TP53-mutant clonal hematopoiesis
Chan ICC, Zhang P, Pan X et al. · Nature genetics 2026 · PMID 41814002 · doi:10.1038/s41588-026-02526-w
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Also filed as BioProject PRJNA1206696 and SRA study SRP555355. Searching any of these in the dataset finder brings you back here.

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