{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T17:32:03Z","timestamp":1761845523467,"version":"build-2065373602"},"reference-count":48,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T00:00:00Z","timestamp":1644883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["842\/10-1","842\/10-2","2531\/2-1","2531\/2-2"],"award-info":[{"award-number":["842\/10-1","842\/10-2","2531\/2-1","2531\/2-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Foundation Leducq","award":["19CVD02"],"award-info":[{"award-number":["19CVD02"]}]},{"name":"Gerdes Stiftung","award":["11000286","19314900"],"award-info":[{"award-number":["11000286","19314900"]}]},{"name":"Hector-Stiftung","award":["M85"],"award-info":[{"award-number":["M85"]}]},{"name":"REBIRTH I\/II (MWK)","award":["ZN3440"],"award-info":[{"award-number":["ZN3440"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Targeted therapies are currently considered the best cost\u2013benefit anti-cancer treatment. In hematological malignancies, however, relapse rates and non-hematopoietic side effects including cardiotoxicity remain high. Here, we describe significant heart damage due to advanced acute lymphoblastic leukemia (ALL) with t(9;22) encoding the bcr-abl oncogene (BCR-ABL+ ALL) in murine xenotransplantation models. Echocardiography reveals severe cardiac dysfunction with impaired left ventricular function and reduced heart and cardiomyocyte dimensions associated with increased apoptosis. This cardiac damage is fully reversible, but cardiac recovery depends on the therapy used to induce ALL remission. Chemotherapy-free combination therapy with dasatinib (DAS), venetoclax (VEN) (targeting the BCR-ABL oncoprotein and mitochondrial B-cell CLL\/Lymphoma 2 (BCL2), respectively), and dexamethasone (DEX) can fully revert cardiac defects, whereas the depletion of otherwise identical ALL in a genetic model using herpes simplex virus type 1 thymidine kinase (HSV-TK) cannot. Mechanistically, dexamethasone induces a pro-apoptotic BCL2-interacting mediator of cell death (BIM) expression and apoptosis in ALL cells but enhances pro-survival B-cell lymphoma extra-large (BCLXL) expression in cardiomyocytes and clinical recovery with the reversion of cardiac atrophy. These data demonstrate that therapies designed to optimize apoptosis induction in ALL may circumvent cardiac on-target side effects and may even activate cardiac recovery. In the future, combining the careful clinical monitoring of cardiotoxicity in leukemic patients with the further characterization of organ-specific side effects and signaling pathways activated by malignancy and\/or anti-tumor therapies seems reasonable.<\/jats:p>","DOI":"10.3390\/cancers14040983","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T22:43:22Z","timestamp":1644965002000},"page":"983","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Chemotherapy-Free Targeted Anti-BCR-ABL+ Acute Lymphoblastic Leukemia Therapy May Benefit the Heart"],"prefix":"10.3390","volume":"14","author":[{"given":"Hanna","family":"Kirchhoff","sequence":"first","affiliation":[{"name":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5479-2275","authenticated-orcid":false,"given":"Melanie","family":"Ricke-Hoch","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Wohlan","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany"},{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Pietzsch","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany"},{"name":"Department of Human Genetics, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0062-3753","authenticated-orcid":false,"given":"\u00dcmran","family":"Karsli","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany"},{"name":"Department of Gastroenterology, Hepatology & Endocrinology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sergej","family":"Erschow","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4656-0770","authenticated-orcid":false,"given":"Robert","family":"Zweigerdt","sequence":"additional","affiliation":[{"name":"Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnold","family":"Ganser","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Eder","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela","family":"Scherr","sequence":"additional","affiliation":[{"name":"Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Denise","family":"Hilfiker-Kleiner","sequence":"additional","affiliation":[{"name":"Department of Cardiology and Angiology, Hannover Medical School, 30625 Hannover, Germany"},{"name":"Department of Cardiovascular Complications of Oncologic Therapies, Medical Faculty of the Philipps University Marburg, 35037 Marburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S1040-8428(00)00097-4","article-title":"Recent approaches in acute lymphoblastic leukemia in adults","volume":"36","author":"Hoelzer","year":"2000","journal-title":"Critk. 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