E-GEOD-36938 - Engineering ABT-737 Resistance in MYC-driven Lymphomas Identifies DHX9 as a Drug Response Modifier

Status
Released on 3 April 2013, last updated on 2 June 2014
Organism
Mus musculus
Samples (6)
Array (1)
Protocols (8)
Description
Many traditional cytotoxic agents used in the treatment of cancer function by eliciting an apoptotic response in tumor cells. However, evasion of apoptosis by BCL-2 family members is often deregulated prior to therapeutic intervention leading to treatment failure. To address this, ABT-737 was rationally designed to target BCL-2-like family members and has shown promising results against tumor cells dependent on BCL-2 for their survival. One shortcoming is that MCL-1, a member of the BCL-2 family is poorly inhibited by ABT-737 and is a major cause of resistance. To gain insight into biological pathways that could circumvent this resistance, we designed an shRNA screen to identify novel sensitizers to ABT-737 by engineering MYC driven lymphomas that were resistant to ABT-737 due to endogenous MCL-1 expression. Utilizing this model, we performed a shRNA drop-out screen and identified Dhx9 as a target whose suppression sensitizes cells to ABT-737. DHX9 loss lead to replicative stress signaling, which in turn potently induced the BH3-only proteins, NOXA and PUMA, in a p53-dependent manner to curtail MCL-1 activity. Induction of NOXA is essential for ABT-737 sensitization. Our results ascribe a novel role for DHX9 in the replicative stress pathway and link DHX9 activity to p53 function in vivo. Comparison of Arf-/-Eu-myc/Bcl-2 lymphomas expressing either control Rluc.713 or Dhx9 shRNA, Dhx9.1241
Experiment type
transcription profiling by array 
Contacts
MIAME
PlatformsProtocolsFactorsProcessedRaw
Files
Investigation descriptionE-GEOD-36938.idf.txt
Sample and data relationshipE-GEOD-36938.sdrf.txt
Raw data (1)E-GEOD-36938.raw.1.zip
Processed data (1)E-GEOD-36938.processed.1.zip
Array designA-GEOD-11078.adf.txt
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