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Series GSE81148 Query DataSets for GSE81148
Status Public on Jun 20, 2016
Title RNASeq of MV4;11 cells transduced with scramble shRNA or BRD4 shRNA in combination with DMSO or SGC0946
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Central to the molecular pathogenesis of MLL leukaemia is the abnormal co-optation of members of transcription complexes including disrupter of telomeric silencing 1-like (DOT1L) and bromodomain containing protein 4 (BRD4). Consequently, targeted therapies against DOT1L and BRD4 are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukaemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation we find that native BRD4 and DOT1L exist in largely separate protein complexes. Genetic disruption or small molecule inhibition of BRD4 and DOT1L shows marked synergistic activity against MLL-FP leukaemia cell lines, primary human leukaemia cells and murine leukaemia models. Mechanistically, we find a previously unrecognised functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in close proximity to superenhancers. DOT1L via H3K79me2 facilitates the deposition of histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide novel insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this poor prognostic disease.
Overall design RNASeq of MV4;11 cells transduced with scramble shRNA or BRD4 shRNA in combination with DMSO or SGC0946 in triplicate
Contributor(s) Dawson M, Gilan O, Lam E
Citation(s) 27294782
Submission date May 05, 2016
Last update date May 15, 2019
Contact name Mark Dawson
Organization name Peter MacCallum Cancer Centre
Street address 305 Grattan Street
City Melbourne
State/province VIC
ZIP/Postal code 3000
Country Australia
Platforms (1)
GPL11154 Illumina HiSeq 2000 (Homo sapiens)
Samples (12)
GSM2143667 DMSO shBRD4 Rep 1
GSM2143668 DMSO shBRD4 Rep 2
GSM2143669 DMSO shBRD4 Rep 3
This SubSeries is part of SuperSeries:
GSE71780 Functional interdependency of BRD4 and DOT1L in MLL leukaemia
BioProject PRJNA320733
SRA SRP074420

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Supplementary file Size Download File type/resource
GSE81148_shRNASeqCPM.txt.gz 993.6 Kb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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