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Altered IFN Signaling and Preserved Susceptibility to Activated Natural Killer Cell–Mediated Lysis of BCR/ABL Targets

¹ Institut National de la Sante et de la Recherche Medicale U487, ² Division of Hematology, ³ Laboratoire de thérapie Cellulaire, Institut Gustave-Roussy; ⁴ Institut National de la Sante et de la Recherche Medicale U542, Hôpital Paul Brousse; and ⁵ UPR9045, Institut Lwoff, Villejuif, France

Requests for reprints: Anne Caignard, Institut National de la Sante et de la Recherche Medicale U487 PR1, Institut Gustave-Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France. Phone: 33-1-42-11-51-56; Fax: 33-1-42-11-52-88; E-mail: caignard{at}igr.fr.

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 IFN, 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 IFN 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 IFN 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 IFN, whereas this pathway is normal in UT-7 and UT-7/E8 cells. A decreased HLA-I induction and nuclear phospho-STAT1 nuclear translocation were also observed in blasts from most chronic myelogenous leukemia patients in response to IFN. These results outline the crucial role of IFN in the control of target cell susceptibility to lysis by activated NK cells and indicate that the altered response to IFN in BCR/ABL targets may preserve these cells from the cytokine-induced negative regulatory effect on their susceptibility to NK-mediated lysis.

Key Words: Chronic myeloid leukemia • IFN • NK cells • cytotoxicity • BCR/ABL • imatinib mesylate

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