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Series GSE58791 Query DataSets for GSE58791
Status Public on Aug 01, 2014
Title Blockade of oncogenic IkappaB kinase activity in ABC DLBCL by small molecule BET protein inhibitors
Organism Homo sapiens
Experiment type Expression profiling by array
Summary In the activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), NF-kappaB activity is essential for viability of the malignant cells and is sustained by constitutive activity of IkappaB kinase (IKK) in the cytoplasm. Here, we report an unexpected role for the bromodomain and extraterminal domain (BET) proteins BRD2 and BRD4 in maintaining oncogenic IKK activity in ABC DLBCL. IKK activity was reduced by small molecules targeting BET proteins as well as by genetic knockdown of BRD2 and BRD4 expression, thereby inhibiting downstream NF-kappaB-driven transcriptional programs and killing ABC DLBCL cells. Using a high-throughput platform to screen for drug-drug synergy, we observed that the BET inhibitor JQ1 combined favorably with multiple drugs targeting B cell receptor signaling, one pathway that activates IKK in ABC DLBCL. The BTK kinase inhibitor ibrutinib, which is in clinical development for the treatment of ABC DLBCL, synergized strongly with BET inhibitors in killing ABC DLBCL cells in vitro and in a xenograft mouse model. These findings provide a mechanistic basis for the clinical development of BET protein inhibitors in ABC DLBCL, particularly in combination with other modulators of oncogenic IKK signaling.
 
Overall design For JQ1 time course gene expression profiling, HBL1 and LP1 cells were treated with either DMSO or 100nM JQ1 for 1h, 3h, 8h, and 24h. For shRNA gene expression profiling, HBL1 cells were infected with either a Ctrl shRNA or with shRNA targeting BRD2 or BRD4. Following puromycin selection, shRNA expression was induced for 1 day and 2 days.
 
Citation(s) 25049379
Submission date Jun 24, 2014
Last update date Mar 27, 2018
Contact name Louis M. Staudt
E-mail(s) lstaudt@mail.nih.gov
Phone 301-402-1892
Organization name National Cancer Institute
Department Lymphoid Malignancies Branch
Lab Louis M Staudt
Street address 9000 Rockville Pike, Bldg 10, Rm 4N114
City Bethesda
State/province MD
ZIP/Postal code 20892
Country USA
 
Platforms (2)
GPL4133 Agilent-014850 Whole Human Genome Microarray 4x44K G4112F (Feature Number version)
GPL16699 Agilent-039494 SurePrint G3 Human GE v2 8x60K Microarray 039381 (Feature Number version)
Samples (12)
GSM1419611 HBL1 JQ1 Treated - 1 hour - mAdbID:117869
GSM1419612 HBL1 JQ1 Treated - 3 hours - mAdbID:117870
GSM1419613 HBL1 JQ1 Treated - 8 hours - mAdbID:117871
Relations
BioProject PRJNA253490

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
GSE58791_RAW.tar 204.9 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table

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