Abstract
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.
Highlights
Acute myeloid leukemia (AML) is characterized by expansion of abnormal myeloid precursor cells in the bone marrow and blood
Using diagnosis and relapse samples from AML patients, patient-derived xenografts (PDX), and leukemia cell lines, we investigated the status of KDM6A during disease progression and the impact of KDM6A loss on chemotherapy resistance
In addition to two previously described cytogenetically normal (CN)-AML patients [3], we identified three patients with recurrent KDM6A mutations using matched diagnosis and relapse samples, which were available for 3/18 patients (Fig. 1b; Supplementary Fig. 1b–d)
Summary
Acute myeloid leukemia (AML) is characterized by expansion of abnormal myeloid precursor cells in the bone marrow and blood. KDM6A is frequently targeted by somatic loss-of-function mutations in cancer [12,13,14,15] including leukemia [16,17,18]. In T-cell acute lymphoblastic leukemia (T-ALL), KDM6A mutations are located almost exclusively in the JmjC domain [16, 17] and inactivation of the single KDM6A copy in males is sufficient to contribute to T-ALL pathogenesis [17]. Using diagnosis and relapse samples from AML patients, patient-derived xenografts (PDX), and leukemia cell lines, we investigated the status of KDM6A during disease progression and the impact of KDM6A loss on chemotherapy resistance. Reduction or loss of KDM6A expression in myeloid cell lines leads to increased resistance towards AraC and DNR treatment. Our findings highlight KDM6A as a novel mediator of drug resistance in AML
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