TY - JOUR
T1 - Wnt/Ca2+/NFAT Signaling Maintains Survival of Ph+ Leukemia Cells upon Inhibition of Bcr-Abl
AU - Gregory, Mark A.
AU - Phang, Tzu L.
AU - Neviani, Paolo
AU - Alvarez-Calderon, Francesca
AU - Eide, Christopher A.
AU - O'Hare, Thomas
AU - Zaberezhnyy, Vadym
AU - Williams, Richard T.
AU - Druker, Brian J.
AU - Perrotti, Danilo
AU - DeGregori, James
N1 - Funding Information:
J.D. is supported by the Leukemia and Lymphoma Society (108692) and the National Cancer Institute (NCI; RO1-CA109657) and M.G. by the Cancer League of Colorado and the NCI (K01-CA133182). D.P. is supported by the NCI (CA095512) and the US Army and CML Research Program (DAMD17-03-1-0184). D.P. is a Scholar of The Leukemia and Lymphoma Society. R.W. is supported by an NIH Cancer Center Support Core Grant (CA-21765), the American Lebanese Syrian Associated Charities, and a Career Development Award from the AACR. We would like to thank Anjana Rao, Jeff Molkentin, Heide Ford, Ulli Bayer, Michael Deininger, and Charles Sherr for providing reagents; Dexiang Gao for statistical analyses; Nidal Boulos for characterization of Arf-null/p185 Bcr-Abl + GFP + cells; Andriy Marusyk, Christopher Porter, and Richard Gregory for comments on the manuscript; Bifeng Gao and Uma Pugazhenthi of the UC Cancer Center Gene Expression Core; and Karen Helm and Christine Childs of the UC Cancer Center Flow Cytometry Core (supported by NIH grant 2P30-CA46934).
PY - 2010/7
Y1 - 2010/7
N2 - 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/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.
AB - 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/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.
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U2 - 10.1016/j.ccr.2010.04.025
DO - 10.1016/j.ccr.2010.04.025
M3 - Article
C2 - 20609354
AN - SCOPUS:77954299059
SN - 1535-6108
VL - 18
SP - 74
EP - 87
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -