Altered IFNγ signaling and preserved susceptibility to activated natural killer cell-mediated lysis of BCR/ABL targets

Christelle Cebo, Ioannis A. Voutsadakis, Sylvie Da Rocha, Jean Henri Bourhis, Abdelali Jalil, Bruno Azzarone, Ali G. Turhan, Mounira Chelbi-Alix, Salem Chouaib, Anne Caignard

Research output: Contribution to journalArticle

Abstract

Previous studies have shown that BCR/ABL oncogene, the molecular counterpart of the Ph1 chromosome, could represent a privileged target to natural killer (NK) cells. In the present study, we showed that activated peripheral NK cells killed high-level BCR/ABL transfectant UT-7/9 derived from the pluripotent hematopoietic cell line UT-7 with a high efficiency. To further define the mechanisms controlling BCR/ABL target susceptibility to NK-mediated lysis, we studied the effect of IFNγ, a key cytokine secreted by activated NK cells, on the lysis of these targets. Treatment of UT-7, UT-7/neo, and low BCR/ABL transfectant UT-7/E8 cells with IFNγ resulted in a dramatic induction of human leukocyte antigen class I (HLA-I) molecules and subsequently in their reduced susceptibility to NK-mediated cytolysis likely as a consequence of inhibitory NK receptors engagement. In contrast, such treatment neither affected HLA-I expression on transfectants expressing high level of BCR/ABL (UT-7/9) nor modulated their lysis by NK cells. Our data further show that the high-level BCR/ABL in UT-7/9 cells display an altered IFNγ signaling, as evidenced by a decrease in IFN regulatory factor-1 (IRF-1) and signal transducers and activators of transcription (STAT) 1 induction and activation in response to IFNγ, whereas this pathway is normal in UT-7 and UT-7/E8 cells. A decreased HLA-I induction and nuclear phosphoSTAT1 nuclear translocation were also observed in blasts from most chronic myelogenous leukemia patients in response to IFNγ. These results outline the crucial role of IFNγ in the control of target cell susceptibility to lysis by activated NK cells and indicate that the altered response to IFNγ in BCR/ABL targets may preserve these cells from the cytokine-induced negative regulatory effect on their susceptibility to NK-mediated lysis.

Original languageEnglish
Pages (from-to)2914-2920
Number of pages7
JournalCancer Research
Volume65
Issue number7
DOIs
Publication statusPublished - Apr 1 2005

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Cebo, C., Voutsadakis, I. A., Da Rocha, S., Bourhis, J. H., Jalil, A., Azzarone, B., Turhan, A. G., Chelbi-Alix, M., Chouaib, S., & Caignard, A. (2005). Altered IFNγ signaling and preserved susceptibility to activated natural killer cell-mediated lysis of BCR/ABL targets. Cancer Research, 65(7), 2914-2920. https://doi.org/10.1158/0008-5472.CAN-04-1932