TP53-mediated therapy-related clonal hematopoiesis contributes to doxorubicin-induced cardiomyopathy by augmenting a neutrophil-mediated cytotoxic response
Soichi Sano, Ying Wang, Hayato Ogawa, Keita Horitani, Miho Sano, Ariel H. Polizio, Anupreet Kour, Yoshimitsu Yura, Heather Doviak, Kenneth Walsh
Soichi Sano, Ying Wang, Hayato Ogawa, Keita Horitani, Miho Sano, Ariel H. Polizio, Anupreet Kour, Yoshimitsu Yura, Heather Doviak, Kenneth Walsh
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Research Article Cardiology

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

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.

Authors

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

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Figure 3

Trp53-deficient myeloid cells accelerate Dox-induced cardiotoxicity.

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Trp53-deficient myeloid cells accelerate Dox-induced cardiotoxicity. (A...
(A) Flow cytometry analysis of cardiac immune cells from mice that underwent competitive BMT and Dox administration. In this study, mice underwent partial (30%) bone marrow reconstitution with Trp53-deficient cells (30% Het BMT mice) or WT cells (30% WT BMT mice). After a 7-week recovery from BMT, mice were injected intraperitoneally with Dox (single injection of 15 μg/g), and hearts were harvested 7 days later for flow cytometry analysis of resident immune cells (n = 6). Statistical analysis was performed with unpaired (2-tailed) Student’s t test (neutrophil) and Mann-Whitney U tests (Ly6Chi monocyte, macrophage). (B) Heatmap of select group of the most highly differentially expressed genes from the highest ranked annotation categories comparing blood neutrophils between Trp53-sufficient (Trp53+/+) and Trp53 heterozygous–deficient mice (Trp53+/–) at 1 day after Dox administration (15 μg/g single injection). Mice were administered Dox by intraperitoneal injection (15 mg/kg split into 3 injections over 10 days). (C) Echocardiographic analysis of left ventricular posterior wall thickness diameter (LVPWTd; mm), fractional shortening (FS; %), left ventricular end-systolic diameter (LVDs; mm), left ventricular end-diastolic diameter (LVDd; mm), and left ventricular mass (LV mass; mg) of myeloid-specific Trp53-deficient (Lyz2Cre/+Tp53fl/f) mice and littermate controls (Control) before and at 8 weeks after Dox administration. Statistical analysis was performed with 2-way repeated-measures ANOVA with Sidak’s multiple-comparisons tests (n = 7 per group). (D) Survival of myeloid-specific Trp53-deficient mice and littermate controls after Dox administration. Survival curve was obtained by the Kaplan-Meier method. Statistical analysis was performed with log-rank test (n = 12 per genotype). (E) Real-time qPCR analysis of transcript expression in myocardium obtained from Lyz2Cre/+Trp53fl/fl and littermate control mice at 8 weeks after Dox treatment (n = 7 per genotype). Statistical analysis was performed with unpaired (2-tailed) Student’s t test (Il6, Il1b, b/a MHC), 2-tailed unpaired Student’s t test with Welch correction (Nppa), or Mann-Whitney U test (Tnf). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.