The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice

Abstract

Rationale: Cancer therapy can be associated with short- and long-term cardiac dysfunction. Cancer patients often exhibit therapy-related clonal hematopoiesis (t-CH), an aggressive form of clonal hematopoiesis that can result from somatic mutations in genes encoding regulators of the DNA-damage response (DDR) pathway. Gain-of-function mutations in exon 6 the protein phosphatase Mg2+/Mn2+ dependent 1D (PPM1D) gene are the most frequently mutated DDR gene associated with t-CH. Whether t-CH can contribute to cardiac dysfunction is unknown. Objective: We evaluated the causal and mechanistic relationships between Ppm1d-mediated t-CH and non-ischemic heart failure in an experimental system. Methods and Results: To test whether gain-of-function hematopoietic cell mutations in Ppm1d can increase the susceptibility to cardiac stress, we evaluated cardiac dysfunction in a mouse model where clonal hematopoiesis-associated mutations in exon 6 of Ppm1d were produced by CRISPR-Cas9 technology. Mice transplanted with hematopoietic stem cells containing the mutated Ppm1d gene exhibited augmented cardiac remodeling following the continuous infusion of angiotensin II (AngII). Ppm1d-mutant macrophages were impaired in DDR pathway activation and displayed greater DNA damage, higher reactive oxygen species generation and an augmented proinflammatory profile with elevations in IL-1β and IL-18. The administration of an NLRP3 inflammasome inhibitor to mice reversed the cardiac phenotype induced by the Ppm1d-mutated hematopoietic stem cells under conditions of AngII-induced stress. Conclusions: A mouse model of Ppm1d-mediated t-CH was more susceptible to cardiac stress. Mechanistically, disruption of the DDR pathway led to elevations in inflammatory cytokine production, and the NLRP3 inflammasome was shown to be essential for this augmented cardiac stress response. These data indicate that t-CH involving activating mutations in PPM1D can contribute to the cardiac dysfunction observed in cancer survivors, and that anti-inflammatory therapy may have utility in treating this condition.

Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality

“…The observation of profibrotic signaling in mLOY is unexpected compared with findings of how CHIP mechanistically contributes to cardiovascular disease. Whereas there is a high co-occurrence of mLOY with CHIP ( 5 , 6 ), and both are associated with cardiovascular disease mortality, including heart failure ( 17 , 18 ), CHIP appears to largely promote pathological processes through the overactivation of IL-1β/IL-6 inflammatory signaling in myeloid cells ( 19 – 22 ). It is increasingly recognized that chronic diseases are caused by a spectrum of inflammation- and fibrosis-driven events ( 23 ).…”

Clonal Hematopoiesis Analyses in Clinical, Epidemiologic, and Genetic Aging Studies to Unravel Underlying Mechanisms of Age-Related Dysfunction in Humans

“…Inhibition of the NLRP3 inflammasome has been shown to mitigate atherosclerosis among hypercholesterolemic mice transplanted with the TET2−/− bone marrow ( Fuster et al, 2020 ). More recently, these experimental studies have been expanded to other CVD models and to other driver genes, including DNMT3A, JAK2, TP53 and PPM1D ( Sano et al, 2018c ; Sano et al, 2019 ; Fidler et al, 2021 ; Sano and Walsh, 2021 ; Yura et al, 2021 ). Collectively, these data indicate that clonal hematopoiesis leads to the overactivation of inflammatory responses in a gene-specific manner.…”

Clinical Significance of Clonal Hematopoiesis of Indeterminate Potential in Hematology and Cardiovascular Disease

“…Importantly, the data on the association of CHIP and cardiovascular disease do not only rely on association studies but also build on multiple lines of evidence from in vitro and in vivo models showing a mechanistic link between somatic mutations in CHIP, proinflammatory state of myeloid cells and inflammation-induced effects on atherosclerosis and cardiac remodeling [ 42 , 64 , 65 , 66 , 67 ]. The majority of these models focused on the effect of TET2 loss or mutations while the mechanistic role of DNMT3A - or ASXL1 -mutated CHIP in cardiovascular disease development is less well understood [ 10 ].…”