RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an E mu-myc/Bcl-2 mouse model

Mills, J. R., Malina, A., Lee, T., Di Paola, D., Larsson, O., Miething, C., Grosse, F., Tang, H. L., Zannis-Hadjopoulos, M., Lowe, S. W., Pelletier, J. (April 2013) RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an E mu-myc/Bcl-2 mouse model. Blood, 121 (17). pp. 3402-3412. ISSN 0006-4971

URL: http://www.ncbi.nlm.nih.gov/pubmed/23440244
DOI: 10.1182/blood-2012-06-434365

Abstract

BT-737 is a promising chemotherapeutic agent that promotes apoptosis by acting as a selective BH3 mimetic to neutralize Bcl-2–like family members. One shortcoming with its use is that Mcl-1, a member of the Bcl-2 family, is poorly inhibited by ABT-737 and thus is a major cause of resistance. We performed a short hairpin RNA (shRNA)-based drop-out screen to identify novel genes and pathways that could reverse resistance to ABT-737 treatment in Eµ-myc/Bcl-2 lymphoma cells engineered to rely on endogenous Mcl-1 for survival. Several drug-sensitive shRNAs were identified that were selectively depleted in the presence of ABT-737. Of these, 2 independent shRNAs targeting the RNA/DNA helicase Dhx9 were found to sensitize lymphomas to ABT-737 to an extent comparable to control Mcl-1 shRNAs. Although Dhx9 suppression sensitized both mouse and human cells to ABT-737 treatment, it did so without altering MCL-1 levels. Rather, loss of Dhx9 appeared to activate a p53-dependent apoptotic program, through aggravation of replicative stress, which was found to be both necessary and sufficient for the ABT-737–shDhx9 synthetic lethal relationship.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > RNAi
organs, tissues, organelles, cell types and functions > cell types and functions > cell functions > apoptosis
organism description > animal > mammal > rodent > mouse
CSHL Authors:
Communities: CSHL labs > Lowe lab
Depositing User: Matt Covey
Date: 25 April 2013
Date Deposited: 16 Aug 2013 18:35
Last Modified: 16 Aug 2013 18:35
PMCID: PMC3637015
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28552

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