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

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

doi:10.1172/jci.insight.146076

Cited by 50 publications

(41 citation statements)

References 41 publications

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“…While concerns can been raised about CH being a risk marker of aging instead of a disease‐driving factor, several studies have shown that CH is independently associated with increased cardiovascular risk after adjusting for age 10,14 . CH has also been shown to have a causal effect in mice harboring either Dnmt3a , Tet2, Jak2, Tp53 , and Ppm1d mutations with adverse LV remodeling, lower LV ejection fraction and worsening degree of fibrosis post‐myocardial infarction 15,18–21 …”

Section: Discussionmentioning

confidence: 99%

Clonal hematopoiesis confers an increased mortality risk in orthotopic heart transplant recipients

Scolari

Brahmbhatt

Abelson

et al. 2022

American Journal of Transplantation

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Novel risk stratification and non-invasive surveillance methods are needed in orthotopic heart transplant (OHT) to reduce morbidity and mortality post-transplant. Clonal hematopoiesis (CH) refers to the acquisition of specific gene mutations in hematopoietic stem cells linked to enhanced inflammation and worse cardiovascular outcomes.The purpose of this study was to investigate the association between CH and OHT.Blood samples were collected from 127 OHT recipients. Error-corrected sequencing was used to detect CH-associated mutations. We evaluated the association between CH and acute cellular rejection, CMV infection, cardiac allograft vasculopathy (CAV), malignancies, and survival. CH mutations were detected in 26 (20.5%) patients, mostly in DNMT3A, ASXL1, and TET2. Patients with CH showed a higher frequency of CAV grade 2 or 3 (0% vs. 18%, p < .001). Moreover, a higher mortality rate was observed in patients with CH (11 [42%] vs. 15 [15%], p = .008) with an adjusted hazard ratio of 2.9 (95% CI, 1.4-6.3; p = .003). CH was not associated with acute cellular rejection, CMV infection or malignancies. The prevalence of CH in OHT recipients is higher than

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Section: Discussionmentioning

confidence: 99%

Clonal hematopoiesis confers an increased mortality risk in orthotopic heart transplant recipients

Scolari

Brahmbhatt

Abelson

et al. 2022

American Journal of Transplantation

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“…TP53 encodes tumor suppressor p53 that is induced by various stress stimuli, including UV IR, DNA double-stranded breaks, and oxidative stress. TP53 coordinates the transcription of genes involved in DNA damage repair, apoptosis, growth arrest, or senescence, and the dysregulation of p53 poses a risk for developing cancers, CVD, and other metabolic disorders 26,27 . While the clones identified in this astronaut cohort are relatively small, there is a possibility for increased clonal instability with aging that may be facilitated by co-mutations in other driver genes.…”

Section: Discussionmentioning

confidence: 99%

Retrospective analysis of somatic mutations and clonal hematopoiesis in astronauts

et al. 2022

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With planned deep space and commercial spaceflights, gaps remain to address health risks in astronauts. Multiple studies have shown associations between clonal expansion of hematopoietic cells with hematopoietic malignancies and cardiometabolic disease. This expansion of clones in the absence of overt hematopoietic disorders is termed clonal hematopoiesis (CH) of indeterminate potential (CHIP). Using deep, error-corrected, targeted DNA sequencing we assayed for somatic mutations in CH-driver genes in peripheral blood mononuclear cells isolated from de-identified blood samples collected from 14 astronauts who flew Shuttle missions between 1998–2001. We identified 34 nonsynonymous mutations of relatively low variant allele fraction in 17 CH-driver genes, with the most prevalent mutations in TP53 and DNMT3A. The presence of these small clones in the blood of relatively young astronaut cohort warrants further retrospective and prospective investigation of their clinical relevance and potential application in monitoring astronaut’s health.

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“…Accordingly, pharmacological inhibition of p53 or Bax blocks apoptosis and prevents DOX-induced cardiomyopathy ( 54 , 55 ). It is noteworthy that p53 plays complicated roles in DOX-induced cardiotoxicity by modulating apoptosis-independent processes including mitochondrial biogenesis ( 56 ) and clonal hematopoiesis ( 57 ), as well as atrophy ( 46 ). In addition to the pore-forming effectors Bak and Bax, the pro-apoptotic Bcl2 family proteins also include activators (Bim, Bid, and Puma) that directly interact with the effectors to trigger apoptosis ( 58 ).…”

Section: Contributions Of Programmed Cell Death To Anthracycline Cardiotoxicitymentioning

confidence: 99%

Novel Mechanisms of Anthracycline-Induced Cardiovascular Toxicity: A Focus on Thrombosis, Cardiac Atrophy, and Programmed Cell Death

Antoniak

Phungphong

Cheng

et al. 2022

Front. Cardiovasc. Med.

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Anthracycline antineoplastic agents such as doxorubicin are widely used and highly effective component of adjuvant chemotherapy for breast cancer and curative regimens for lymphomas, leukemias, and sarcomas. The primary dose-limiting adverse effect of anthracyclines is cardiotoxicity that typically manifests as cardiomyopathy and can progress to the potentially fatal clinical syndrome of heart failure. Decades of pre-clinical research have explicated the complex and multifaceted mechanisms of anthracycline-induced cardiotoxicity. It is well-established that oxidative stress contributes to the pathobiology and recent work has elucidated important central roles for direct mitochondrial injury and iron overload. Here we focus instead on emerging aspects of anthracycline-induced cardiotoxicity that may have received less attention in other recent reviews: thrombosis, myocardial atrophy, and non-apoptotic programmed cell death.

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

Cited by 50 publications

References 41 publications

Clonal hematopoiesis confers an increased mortality risk in orthotopic heart transplant recipients

Clonal hematopoiesis confers an increased mortality risk in orthotopic heart transplant recipients

Retrospective analysis of somatic mutations and clonal hematopoiesis in astronauts

Novel Mechanisms of Anthracycline-Induced Cardiovascular Toxicity: A Focus on Thrombosis, Cardiac Atrophy, and Programmed Cell Death

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