GenomeRNAi - a database for RNAi phenotypes and reagents
TitleScreen TitleAssayBiomodelSpecies
Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Gregory et al. (2010) Combinatorial effect with imatinib Viability (synthetic lethal)K562H. sapiens


Although Bcr-Abl kinase inhibitors have proven effective in the treatment of chronic myeloid leukemia (CML), they generally fail to eradicate Bcr-Abl(+) leukemia cells. To identify genes whose inhibition sensitizes Bcr-Abl(+) leukemias to killing by Bcr-Abl inhibitors, we performed an RNAi-based synthetic lethal screen with imatinib mesylate in CML cells. This screen identified numerous components of a Wnt/Ca(2+)/NFAT signaling pathway. Antagonism of this pathway led to impaired NFAT activity, decreased cytokine production, and enhanced sensitivity to Bcr-Abl inhibition. Furthermore, NFAT inhibition with cyclosporin A facilitated leukemia cell elimination by the Bcr-Abl inhibitor dasatinib and markedly improved survival in a mouse model of Bcr-Abl(+) acute lymphoblastic leukemia (ALL). Targeting this pathway in combination with Bcr-Abl inhibition could improve treatment of Bcr-Abl(+) leukemias.

Screen details

Stable Id: GR00181-A
Screen title: Combinatorial effect with imatinib
Assay: Viability (synthetic lethal)
Method: PCR and Affymetrix microarray
Scope: Random genes
Screen type: Cell-based
Species: Homo sapiens
Biosource: Cell line
Biomodel: K562
Library: System Biosciences, GeneNet lentiviral human 50K shRNA library
Reagent type: shRNA
Score type: Fold change
Cutoff: Complex criteria