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Stief, S.M.* ; Hanneforth, A.L.* ; Weser, S.* ; Mattes, R.* ; Carlet, M. ; Liu, W.-H. ; Bartoschek, M.D.* ; Domínguez Moreno, H.* ; Oettle, M.* ; Kempf, J.* ; Vick, B. ; Ksienzyk, B.* ; Tizazu, B.* ; Rothenberg-Thurley, M.* ; Quentmeier, H.* ; Hiddemann, W.* ; Vosberg, S.* ; Greif, P.A.* ; Metzeler, K.H.* ; Schotta, G.* ; Bultmann, S.* ; Jeremias, I. ; Leonhardt, H.* ; Spiekermann, K.*

Loss of KDM6A confers drug resistance in acute myeloid leukemia.

Leukemia 34, 50-62 (2020)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Gene-mutations; Utx; Demethylases; Daunorubicin; Enhancers; Spectrum; Jmjd3
ISSN (print) / ISBN 0887-6924
e-ISSN 1476-5551
Journal Leukemia
Quellenangaben Volume: 34, Issue: 1, Pages: 50-62 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place Macmillan Building, 4 Crinan St, London N1 9xw, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Research Unit Apoptosis in Hematopoietic Stem Cells (AHS)