RNAi screening uncovers Dhx9 as a modifier of ABT-737 resistance in an Eµ-myc/Bcl-2 mouse model.
Blood
; 121(17): 3402-12, 2013 Apr 25.
Article
em En
| MEDLINE
| ID: mdl-23440244
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Sulfonamidas
/
Compostos de Bifenilo
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Proteínas Proto-Oncogênicas c-myc
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Resistencia a Medicamentos Antineoplásicos
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Proteínas Proto-Oncogênicas c-bcl-2
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Interferência de RNA
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Modelos Animais de Doenças
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RNA Helicases DEAD-box
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Linfoma
/
Nitrofenóis
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
/
Screening_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Blood
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Canadá