کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2107717 | 1083696 | 2010 | 14 صفحه PDF | دانلود رایگان |
SummaryAlthough 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.
► 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
Journal: - Volume 18, Issue 1, 13 July 2010, Pages 74–87