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Series GSE128261 Query DataSets for GSE128261
Status Public on Jun 18, 2019
Title Loss of DKM6A confers drug resistance in acute myeloid leukemia (ChIP-seq of AML cell lines K562 and THP-1)
Organism Homo sapiens
Experiment type Genome binding/occupancy profiling by high throughput sequencing
Summary 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-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). 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.
Overall design H3K27ac ChIP-seq of AML cell lines K562 and THP-1
Contributor(s) Stief SM, Hanneforth A, Mattes R, Weser S, Carlet M, Liu W, Bartoschek MD, Domínguez Moreno H, Oettle M, Vick B, Ksienyzk B, Kempf J, Tizazu B, Rothenberg-Thurley M, Quentmeier H, Hiddemann W, Vosberg S, Greif P, Metzeler KH, Schotta G, Bultmann S, Jeremias I, Leonhardt H, Spiekermann K
Citation(s) 31201358
Submission date Mar 13, 2019
Last update date Jun 18, 2019
Contact name Helena Domínguez Moreno
Organization name Biomedical Center of LMU
Department Molecular Biology
Lab AG Schotta
Street address Großhaderner Str. 9
City Planegg
State/province Bavaria
ZIP/Postal code 82152
Country Germany
Platforms (1)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
Samples (5)
GSM3669509 GS702 K562 WT H3K27ac ChIPseq
GSM3669510 GS703 K562 KDM6A KO PB KDM6A H3K27ac ChIPseq
GSM3669511 GS704 K562 KDM6A KO PB KDM6A+doxy H3K27ac ChIPseq
This SubSeries is part of SuperSeries:
GSE128262 Loss of DKM6A confers drug resistance in acute myeloid leukemia
BioProject PRJNA526902
SRA SRP188360

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE128261_RAW.tar 1.4 Gb (http)(custom) TAR (of BIGWIG)
SRA Run SelectorHelp
Raw data are available in SRA
Processed data provided as supplementary file

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