title: Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl.
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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gregory
authors.forename: Tzu L
authors.initials: TL
authors.lastname: Phang
authors.forename: Paolo
authors.initials: P
authors.lastname: Neviani
authors.forename: Francesca
authors.initials: F
authors.lastname: Alvarez-Calderon
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Eide
authors.forename: Thomas
authors.initials: T
authors.lastname: O'Hare
authors.forename: Vadym
authors.initials: V
authors.lastname: Zaberezhnyy
authors.forename: Richard T
authors.initials: RT
authors.lastname: Williams
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: Danilo
authors.initials: D
authors.lastname: Perrotti
authors.forename: James
authors.initials: J
authors.lastname: Degregori
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis; D001549:Benzamides; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D049109:Cell Proliferation; D016572:Cyclosporine / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D000069439:Dasatinib; D005260:Female; D005434:Flow Cytometry; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate; D007166:Immunosuppressive Agents / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D001549:Benzamides; D016207:Cytokines; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D013844:Thiazoles; D051153:Wnt Proteins; D016572:Cyclosporine; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib; D002118:Calcium