Details

Autor(en) / Beteiligte

• Gregory, Mark A.
• Phang, Tzu L.
• Neviani, Paolo
• Alvarez-Calderon, Francesca
• Eide, Christopher A.
• O'Hare, Thomas
• Zaberezhnyy, Vadym
• Williams, Richard T.
• Druker, Brian J.
• Perrotti, Danilo
• DeGregori, James

Titel

Wnt/Ca 2+/NFAT Signaling Maintains Survival of Ph + Leukemia Cells upon Inhibition of Bcr-Abl

Ist Teil von

• Cancer cell, 2010, Vol.18 (1), p.74-87

Ort / Verlag

Elsevier Inc

Erscheinungsjahr

2010

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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. ► RNAi screen identifies targets that are synthetic lethal with Bcr-Abl inhibitors ► Bcr-Abl inhibition reveals a role for Wnt/NFAT signaling in leukemia cell survival ► Inhibition of NFAT signaling improves treatment of Bcr-Abl + leukemia in mice