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| 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
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| 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.
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| Overall design |
H3K27ac ChIP-seq of AML cell lines K562 and THP-1
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| 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 |
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| Submission date |
Mar 13, 2019 |
| Last update date |
Jun 18, 2019 |
| Contact name |
Helena Domínguez Moreno |
| Organization name |
Biomedical Center of LMU
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| Department |
Molecular Biology
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| Lab |
AG Schotta
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| Street address |
Großhaderner Str. 9
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| City |
Planegg |
| State/province |
Bavaria |
| ZIP/Postal code |
82152 |
| Country |
Germany |
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| Platforms (1) |
| GPL18460 |
Illumina HiSeq 1500 (Homo sapiens) |
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| Samples (5)
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| 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 |
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| This SubSeries is part of SuperSeries: |
| GSE128262 |
Loss of DKM6A confers drug resistance in acute myeloid leukemia |
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| Relations |
| BioProject |
PRJNA526902 |
| SRA |
SRP188360 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE128261_RAW.tar |
1.4 Gb |
(http)(custom) |
TAR (of BIGWIG) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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