Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl.
Cancer Cell
; 18(1): 74-87, 2010 Jul 13.
Article
em En
| MEDLINE
| ID: mdl-20609354
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.
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Base de dados:
MEDLINE
Assunto principal:
Cromossomo Filadélfia
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Leucemia Mielogênica Crônica BCR-ABL Positiva
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Cálcio
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Proteínas de Fusão bcr-abl
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Proteínas Wnt
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Fatores de Transcrição NFATC
Idioma:
En
Ano de publicação:
2010
Tipo de documento:
Article