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.
authors: Department of Biochemistry McGill University, Montreal, Quebec, Canada.
authors: John R
authors: JR
authors: Mills
authors: Abba
authors: A
authors: Malina
authors: Teresa
authors: T
authors: Lee
authors: Domenic
authors: D
authors: Di Paola
authors: Ola
authors: O
authors: Larsson
authors: Cornelius
authors: C
authors: Miething
authors: Frank
authors: F
authors: Grosse
authors: Hengli
authors: H
authors: Tang
authors: Maria
authors: M
authors: Zannis-Hadjopoulos
authors: Scott W
authors: SW
authors: Lowe
authors: Jerry
authors: J
authors: Pelletier
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002453:Cell Cycle; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000502:physiology; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D060045:Genes, Modifier; D006801:Humans; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D051379:Mice; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D034622:RNA Interference; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; C506727:Dhx9 protein, mouse; C579094:Mcl1 protein, mouse; C489428:Myc protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D013449:Sulfonamides; D053487:DEAD-box RNA Helicases