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Series GSE81149 Query DataSets for GSE81149
Status Public on Jun 20, 2016
Title RNASeq of MLL-AF9 cells transduced with scramle shRNA or BRD4 shRNA in combination with DMSO or SGC0946
Organism Mus musculus
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 MLL-AF9 cells transduced with scramle 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
E-mail(s) mark.dawson@petermac.org
Organization name Peter MacCallum Cancer Centre
Street address 305 Grattan Street
City Melbourne
State/province VIC
ZIP/Postal code 3000
Country Australia
 
Platforms (1)
GPL13112 Illumina HiSeq 2000 (Mus musculus)
Samples (10)
GSM2143679 shSCRAM Rep 1
GSM2143680 shSCRAM Rep 2
GSM2143681 shSCRAM Rep 3
This SubSeries is part of SuperSeries:
GSE71780 Functional interdependency of BRD4 and DOT1L in MLL leukaemia
Relations
BioProject PRJNA320736
SRA SRP074419

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

Supplementary file Size Download File type/resource
GSE81149_MLLAF9shRNASeqCPM.txt.gz 644.0 Kb (ftp)(http) TXT
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

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