TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response in a murine model

Therapy-related clonal hematopoiesis (t-CH) is often observed in cancer survivors. This form of clonal hematopoiesis typically involves somatic mutations in driver genes that encode components of the DNA damage response (DDR) and confer hematopoietic stem and progenitor cells (HSPC) with resistance to the genotoxic stress of the cancer therapy. A model of TP53-mediated t-CH was established through the transfer of Trp53-mutant HSPC to mice followed by treatment with a course of the chemotherapeutic agent doxorubicin. These studies revealed that neutrophil infiltration in the heart significantly contributes to doxorubicin-induced cardiac toxicity and that this condition is amplified in the model of Trp53-mediated t-CH. These data suggest t-CH could contribute to the elevated heart failure risk that occurs in cancer survivors. Overall design: Peripheral blood neutrophils of Trp53-sufficient mice and Trp53- heterozygous deficient mice at 1 day after Dox injection (n=4 per genotype) were used for RNA isolation for sequencing.