Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl

Cancer Cell. 2010 Jul 13;18(1):74-87. doi: 10.1016/j.ccr.2010.04.025.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Benzamides
  • Blotting, Western
  • Calcium / metabolism*
  • Cell Proliferation
  • Cyclosporine / pharmacology
  • Cytokines / metabolism
  • Dasatinib
  • Female
  • Flow Cytometry
  • Fusion Proteins, bcr-abl / antagonists & inhibitors*
  • Fusion Proteins, bcr-abl / genetics
  • Fusion Proteins, bcr-abl / metabolism
  • Humans
  • Imatinib Mesylate
  • Immunosuppressive Agents / pharmacology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mice
  • Mice, Inbred C57BL
  • NFATC Transcription Factors / genetics
  • NFATC Transcription Factors / metabolism*
  • Philadelphia Chromosome*
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology
  • Pyrimidines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Small Interfering / pharmacology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Thiazoles / pharmacology
  • Tumor Cells, Cultured
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism*

Substances

  • Benzamides
  • Cytokines
  • Immunosuppressive Agents
  • NFATC Transcription Factors
  • Piperazines
  • Protein Kinase Inhibitors
  • Pyrimidines
  • RNA, Messenger
  • RNA, Small Interfering
  • Thiazoles
  • Wnt Proteins
  • Cyclosporine
  • Imatinib Mesylate
  • Fusion Proteins, bcr-abl
  • Dasatinib
  • Calcium

Associated data

  • GEO/GSE21499