Author/Authors :
Gregory، نويسنده , , Mark A. and Phang، نويسنده , , Tzu L. and Neviani، نويسنده , , Paolo and Alvarez-Calderon، نويسنده , , Francesca and Eide، نويسنده , , Christopher A. and OʹHare، نويسنده , , Thomas and Zaberezhnyy، نويسنده , , Vadym and Williams، نويسنده , , Richard T. and Druker، نويسنده , , Brian J. and Perrotti، نويسنده , , Danilo and DeGregori، نويسنده , , James، نويسنده ,
Abstract :
Summary
gh 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/Ca2+/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.
