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

Soichi Sano,Hayato Ogawa,Ariel H Polizio,Ying Wang,Keita Horitani,Kenneth Walsh,Miho Sano,Anupreet Kour,Yoshimitsu Yura,Heather Doviak

doi:10.1172/jci.insight.146076

Abstract

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 and confer hematopoietic stem and progenitor cells (HSPCs) with resistance to the genotoxic stress of the cancer therapy. Here, we established a model of TP53-mediated t-CH through the transfer of Trp53 mutant HSPCs 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 that t-CH could contribute to the elevated heart failure risk that occurs in cancer survivors who have been treated with genotoxic agents.

Highlights

Anthracyclines, such as doxorubicin (Dox), are an essential component of many treatment regimens for both solid and hematologic cancers
In support of the concept that TP53 is a driver of Therapy-related clonal hematopoiesis (t-CH), Dox administration resulted in the further expansion of Trp53+/– cells but had little or no effect on the minimal expansion of transplanted wild-type cells when circulating cell populations were assessed (Figure 1B)
We report that Dox therapy will lead to the prolonged infiltration of neutrophils to the heart and that neutrophil depletion or inhibition will diminish the cardiotoxic actions of Dox

Summary

Introduction

Anthracyclines, such as doxorubicin (Dox), are an essential component of many treatment regimens for both solid and hematologic cancers. Regardless, mortality due to cardiovascular disease (CVD) in cancer survivors is typically greater than that due to cancer itself after a 10-year follow-up [6], and premature CVD is the leading cause of death among aging people who were treated for cancer as children [7, 8]. This chronic cardiotoxicity is considered to be irreversible, refractory to standard heart failure therapy, and associated with very poor prognosis. There is an obvious need to understand this time-dependent cardiotoxicity and to overcome these hurdles

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Results

Conclusion