RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an Eμ-myc/Bcl-2 mouse model Journal Article
| Authors: | Mills, J. R.; Malina, A.; Lee, T.; Di Paola, D.; Larsson, O.; Miething, C.; Grosse, F.; Tang, H.; Zannis-Hadjopoulos, M.; Lowe, S. W.; Pelletier, J. |
| Article Title: | RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an Eμ-myc/Bcl-2 mouse model |
| Abstract: | ABT-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. |
| Keywords: | genetics; mouse; animal; metabolism; animals; mice; cell cycle; protein bcl 2; rna interference; drug resistance; pathology; drug resistance, neoplasm; physiology; disease model; dead box protein; dead-box rna helicases; drug antagonism; sulfonamide; sulfonamides; myc protein; lymphoma; piperazines; cdkn2a protein, mouse; cyclin dependent kinase inhibitor 2a; cyclin-dependent kinase inhibitor p16; disease models, animal; piperazine derivative; proto-oncogene proteins c-myc; proto-oncogene proteins c-bcl-2; 4 [4 (4' chloro 2 biphenylylmethyl) 1 piperazinyl] n [4 [3 dimethylamino 1 (phenylthiomethyl)propylamino] 3 nitrobenzenesulfonyl]benzamide; nitrophenols; abt-737; biphenyl derivative; nitrophenol; biphenyl compounds; modifier gene; genes, modifier; dhx9 protein, mouse; myc protein, mouse; myeloid cell leukemia sequence 1 protein |
| Journal Title: | Blood |
| Volume: | 121 |
| Issue: | 17 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2013-04-25 |
| Start Page: | 3402 |
| End Page: | 3412 |
| Language: | English |
| DOI: | 10.1182/blood-2012-06-434365 |
| PUBMED: | 23440244 |
| PROVIDER: | scopus |
| PMCID: | PMC3637015 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 2 December 2013" - "Source: Scopus" |
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