IDH1/2 mutations in acute myeloid leukemia patients and risk of coronary artery disease and cardiac dysfunction-a retrospective propensity score analysis.

Autor: Kattih B; Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany.; Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Ludolf-Krehl-Strasse 7-11, 68167, Mannheim, Germany.; Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.; German Center for Cardiovascular Research (DZHK), partner site Rhein/Main, Frankfurt am Main, Germany., Shirvani A; Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Klement P; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Garrido AM; Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Ludolf-Krehl-Strasse 7-11, 68167, Mannheim, Germany., Gabdoulline R; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Liebich A; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Brandes M; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Chaturvedi A; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Seeger T; Department of Medicine III, University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.; German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany., Thol F; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Göhring G; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Schlegelberger B; Department of Human Genetics, Hannover Medical School, Hannover, Germany., Geffers R; Genome Analytics, Helmholtz Center for Infection Research, Braunschweig, Germany., John D; Institute for Cardiovascular Regeneration, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.; German Center for Cardiovascular Research (DZHK), partner site Rhein/Main, Frankfurt am Main, Germany., Bavendiek U; Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Bauersachs J; Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Ganser A; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany., Heineke J; Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany. Joerg.Heineke@medma.uni-heidelberg.de.; Department of Cardiovascular Physiology, European Center for Angioscience (ECAS), Medical Faculty Mannheim of Heidelberg University, Ludolf-Krehl-Strasse 7-11, 68167, Mannheim, Germany. Joerg.Heineke@medma.uni-heidelberg.de.; German Center for Cardiovascular Research (DZHK), partner site Heidelberg/Mannheim, Heidelberg, Germany. Joerg.Heineke@medma.uni-heidelberg.de., Heuser M; Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany. heuser.michael@mh-hannover.de.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2021 May; Vol. 35 (5), pp. 1301-1316. Date of Electronic Publication: 2020 Sep 18.
DOI: 10.1038/s41375-020-01043-x
Abstrakt: Clonal hematopoiesis of indeterminate potential (CHIP) is linked to leukemia gene mutations and associates with an increased risk for coronary artery disease and poor prognosis in ischemic cardiomyopathy. Two recurrently mutated genes in CHIP and adult acute myeloid leukemia (AML) encode for isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). Global expression of mutant IDH2 in transgenic mice-induced dilated cardiomyopathy and muscular dystrophy. In this retrospective observational study, we investigated whether mutant IDH1/2 predisposes to cardiovascular disease in AML patients. Among 363 AML patients, IDH1 and IDH2 mutations were detected in 26 (7.2%) and 39 patients (10.7%), respectively. Mutant IDH1 patients exhibited a significantly higher prevalence of coronary artery disease (26.1% vs. 6.4%, p = 0.002). Applying inverse probability-weighting analysis, patients with IDH1/2 mutations had a higher risk for a declining cardiac function during AML treatment compared to IDH1/2 wild type patients [left ventricular ejection fraction pretreatment compared to 10 months after diagnosis: 59.2% to 41.9% (p < 0.001) vs 58.5% to 55.4% (p = 0.27), respectively]. Mechanistically, RNA sequencing and immunostaining in hiPS-derived cardiomyocytes indicated that the oncometabolite R-2HG exacerbated doxorubicin mediated cardiotoxicity. Evaluation of IDH1/2 mutation status may therefore help identifying AML patients at risk for cardiovascular complications during cytotoxic treatment.
Databáze: MEDLINE
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