Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein

Mice with a null mutation of the gene encoding interferon consensus sequenc e-binding protein (ICSBP) develop a disease with marked expansion of granul ocytes and macrophages that frequently progresses to a fatal blast crisis, thus resembling human chronic myelogenous leukemia (CML). One important fea ture of CML is decreased responsiveness of myeloid cells to apoptotic stimu li. Here we show that myeloid cells from mice deficient in ICSBP exhibit re duced spontaneous apoptosis and a significant decrease in sensitivity to ap optosis induced by DNA damage. In contrast, apoptosis in thymocytes from IC SBP-deficient mice is unaffected. We also show that overexpression of ICSBP in the human U937 monocytic cell line enhances the rate of spontaneous apo ptosis and the sensitivity to apoptosis induced by etoposide, lipopolysacch aride plus ATP, or rapamycin. Programmed cell death induced by etoposide wa s specifically blocked by peptides inhibitory for the caspase-1 or caspase- 3 subfamilies of caspases. Studies of proapoptotic genes showed that cells overexpressing ICSBP have enhanced expression of caspase-3 precursor protei n. In addition, analyses of antiapoptotic genes showed that overexpression of ICSBP results in decreased expression of Bcl-X-L. These data suggest tha t ICSBP modulates survival of myeloid cells by regulating expression of apo ptosis-related genes.