Interferon-gamma prevents apoptosis in Epstein-Barr virus-infected naturalkiller cell leukemia in an autocrine fashion

The significant function of cytokines includes maintenance of cell survival as well as induction of cell differentiation and/or proliferation. We demo nstrate here that interferon-gamma (IFN-gamma) plays a role for progression of Epstein-Barr virus (EBV)-infected natural killer cell leukemia (NK leuk emia) through maintaining cell survival. NK leukemia cells obtained from 7 patients had clonal episomal forms of EBV, indicating that the leukemic cel ls were of clonal origin. Although normal NK cells constitutively expressed Bcl-2, the EBV-infected NK leukemia cells lacked endogenous Bcl-2 expressi on and were hypersensitive to apoptosis in vitro. The addition of IFN-gamma to the culture significantly inhibited their spontaneous apoptosis without inducing cell proliferation or upregulation of Bcl-2. The NK leukemia cell s constitutively secreted IFN-gamma, and the patients' sera contained a hig h concentration of IFN-gamma, levels that were high enough to prevent NK le ukemia cells from apoptosis. Bcl-X-L was not involved in the IFN-gamma-indu ced NK leukemia cell survival. These data suggest that the acquisition of I FN-gamma-mediated autocrine survival signals, other than Bcl-2 or BCL-X-L, might be important for the development of EBV-infected NK leukemia. (C) 199 9 by The American Society of Hematology.