Human Gene Set: GREGORY_SYNTHETIC_LETHAL_WITH_IMATINIB


Standard name GREGORY_SYNTHETIC_LETHAL_WITH_IMATINIB
Systematic name M2137
Brief description Genes identified as synthetic lethal with imatinib [PubChem=5291] in RNAi screen in K562 cells (CML, chronic myelogenous leukemia).
Full description or abstract 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.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 20609354   Authors: Gregory MA,Phang TL,Neviani P,Alvarez-Calderon F,Eide CA,O'Hare T,Zaberezhnyy V,Williams RT,Druker BJ,Perrotti D,Degregori J
Exact source Table 1S
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Organism Homo sapiens
Contributed by Arthur Liberzon (MSigDB Team)
Source platform Human_RefSeq
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Version history 3.1: First introduced

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