Loss of KDM6A confers drug resistance in acute myeloid leukemia.

Autor: Stief SM; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany., Hanneforth AL; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Weser S; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Mattes R; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Carlet M; Department of Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Zentrum München, Munich, Germany., Liu WH; Department of Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Zentrum München, Munich, Germany., Bartoschek MD; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Human Biology and BioImaging, LMU Munich, Planegg-Martinsried, Germany., Domínguez Moreno H; Biomedical Center and Center for Integrated Protein Science Munich, LMU Munich, Martinsried, Germany., Oettle M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Kempf J; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Vick B; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany.; Department of Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Zentrum München, Munich, Germany., Ksienzyk B; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Tizazu B; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Rothenberg-Thurley M; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Quentmeier H; Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ-German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany., Hiddemann W; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Vosberg S; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany., Greif PA; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany.; German Cancer Research Centre (DKFZ), Heidelberg, Germany., Metzeler KH; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany., Schotta G; Biomedical Center and Center for Integrated Protein Science Munich, LMU Munich, Martinsried, Germany., Bultmann S; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Human Biology and BioImaging, LMU Munich, Planegg-Martinsried, Germany., Jeremias I; German Cancer Consortium (DKTK), Heidelberg, Germany.; Department of Apoptosis in Hematopoietic Stem Cells (AHS), Helmholtz Zentrum München, Munich, Germany.; Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU Munich, Munich, Germany., Leonhardt H; Department of Biology II and Center for Integrated Protein Science Munich (CIPSM), Human Biology and BioImaging, LMU Munich, Planegg-Martinsried, Germany., Spiekermann K; Department of Medicine III, University Hospital, LMU Munich, Munich, Germany. karsten.spiekermann@med.uni-muenchen.de.; German Cancer Consortium (DKTK), Heidelberg, Germany. karsten.spiekermann@med.uni-muenchen.de.; German Cancer Research Centre (DKFZ), Heidelberg, Germany. karsten.spiekermann@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2020 Jan; Vol. 34 (1), pp. 50-62. Date of Electronic Publication: 2019 Jun 14.
DOI: 10.1038/s41375-019-0497-6
Abstrakt: Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm resulting from the malignant transformation of myeloid progenitors. Despite intensive chemotherapy leading to initial treatment responses, relapse caused by intrinsic or acquired drug resistance represents a major challenge. Here, we report that histone 3 lysine 27 demethylase KDM6A (UTX) is targeted by inactivating mutations and mutation-independent regulation in relapsed AML. Analyses of matched diagnosis and relapse specimens from individuals with KDM6A mutations showed an outgrowth of the KDM6A mutated tumor population at relapse. KDM6A expression is heterogeneously regulated and relapse-specific loss of KDM6A was observed in 45.7% of CN-AML patients. KDM6A-null myeloid leukemia cells were more resistant to treatment with the chemotherapeutic agents cytarabine (AraC) and daunorubicin. Inducible re-expression of KDM6A in KDM6A-null cell lines suppressed proliferation and sensitized cells again to AraC treatment. RNA expression analysis and functional studies revealed that resistance to AraC was conferred by downregulation of the nucleoside membrane transporter ENT1 (SLC29A1) by reduced H3K27 acetylation at the ENT1 locus. Our results show that loss of KDM6A provides cells with a selective advantage during chemotherapy, which ultimately leads to the observed outgrowth of clones with KDM6A mutations or reduced KDM6A expression at relapse.
Databáze: MEDLINE
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