Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients

Haupt, L.; Maus, A.; Tiburcy, M.; Koehne, S.; Maurer, W.; Tappu, R.; Haas, J.; Li, Y.; Sasse, A.; Santos, C.; Dressel, R.; Wojnowski, L.; Bunt, G.; Shah, A. M.; Meder, B.; Sossalla, S.; Wollnik, B.; Hasenfuss, G.; Streckfuss-Bömeke, K.

doi:10.1101/2020.04.15.042424

bioRxiv · 10.1101/2020.04.15.042424

Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients

Haupt, L.·Maus, A.·Tiburcy, M.·Koehne, S.·Maurer, W.·Tappu, R.·Haas, J.·Li, Y.·Sasse, A.·Santos, C.·Dressel, R.·Wojnowski, L.·Bunt, G.·Shah, A. M.·Meder, B.·Sossalla, S.·Wollnik, B.·Hasenfuss, G.·Streckfuss-Bömeke, K.

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Abstract

Cancer 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.

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Haupt, L., Maus, A., Tiburcy, M., Koehne, S., Maurer, W., Tappu, R., Haas, J., Li, Y., Sasse, A., Santos, C., Dressel, R., Wojnowski, L., Bunt, G., Shah, A. M., Meder, B., Sossalla, S., Wollnik, B., Hasenfuss, G., Streckfuss-Bömeke, K.. 2020-04-17. Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients. https://doi.org/10.1101/2020.04.15.042424

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