Loss of KDM6A confers drug resistance in acute myeloid leukemia
| Autor: | Wen-Hsin Liu, Sophie M. Stief, Philipp A. Greif, Klaus H. Metzeler, Irmela Jeremias, Michael D. Bartoschek, Gunnar Schotta, Michela Carlet, Hilmar Quentmeier, Anna-Li Hanneforth, Heinrich Leonhardt, Maja Rothenberg-Thurley, Wolfgang Hiddemann, Sabrina Weser, Sebastian Vosberg, Karsten Spiekermann, Julia M. Kempf, Sebastian Bultmann, Helena Domínguez Moreno, Binje Vick, Raphael Mattes, Bianka Ksienzyk, Matthias Oettle, Belay Tizazu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cancer Research Myeloid Daunorubicin medicine.medical_treatment Population Drug resistance Article Acute myeloid leukaemia 03 medical and health sciences Mice 0302 clinical medicine medicine Neoplasm Animals Humans education Histone Demethylases Chemotherapy education.field_of_study business.industry Myeloid leukemia Hematology medicine.disease Leukemia Myeloid Acute Cancer therapeutic resistance 030104 developmental biology medicine.anatomical_structure Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Mutation Cytarabine Cancer research Heterografts business medicine.drug |
| Zdroj: | Leukemia Leukemia 34, 50-62 (2020) |
| ISSN: | 1476-5551 |
| Popis: | 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: | OpenAIRE |
| Externí odkaz: |
|
Full text from SpringerLink