Blood. 2013 Feb 25. [Epub ahead of print]
RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an Eµ-myc/Bcl-2 mouse model.
Mills JR, Malina A, Lee T, Di Paola D, Larsson O, Miething C, Grosse F, Tang H, Zannis-Hadjopoulos M, Lowe SW, Pelletier J.
Department of Biochemistry, McGill University, Montreal, QC, Canada;
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 a major cause of resistance. We performed a 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, two 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. |
