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Doxorubicin Induces Cardiotoxicity In A Pluripotent Stem Cell Model Of Aggressive B Cell Lymphoma Cancer Patients

Luis Peter Haupt, Andreas Maus, Malte Tiburcy, Steffen Köhne, Wiebke Maurer, Rewati Tappu, Jan Haas, Yun Li, Andre Sasse, Celio C. X. Santos, Ralf Dressel, L. Wojnowski, Gertrude Bunt, Ajay M. Shah, Benjamin Meder, Samuel Sossalla, Bernd Wollnik, Gerd Hasenfuß, Katrin Streckfuß-Bömeke

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AbstractCancer therapies have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of cancer.ACT-iPSC-CM generated from individuals with CD20+ B-cell lymphoma cancer who had received high doses of DOX and suffered cardiac dysfunction were observed to be persistently more susceptible to DOX toxicity compared to control-iPSC-CM. ACT-iPSC-CM exhibited increased DOX-dependent disorganized myofilament structure and cell death, as well as higher reactive oxygen species (ROS) compared to controls. Importantly, analysis of engineered heart muscle (EHM) from ACT-iPSC-CM showed an impaired DOX-dependent mechanical functionality. Transcriptome profiles of EHM are in line with a disturbed adjustment to DOX-dependent alteration of Ca2+ homeostasis in ACT-iPSC-CM. Furthermore, genetic variants in different cardiac key regulators were uncovered.In conclusion, we developed the first human iPSC-CM and EHM model of DOX-induced cardiac dysfunction in patients with B-cell lymphoma. Our results suggest that DOX-related stress resulted in decreased contractile activity and finally in heart failure in ACT patients.Brief summaryDevelopment of the first human iPSC-CM model of DOX-induced cardiac dysfunction in patients with aggressive B cell lymphoma and high-dose DOX treatment.