Tumors, such as the murine Lewis lung carcinoma (LLC), produce granulocyte-macrophage colony-stimulating factor (GM-CSF), which increases the proportion of CD34 ุ hematopoietic progenitor cells in the bone marrow and in the periphery. This increase in peripheral CD34 ุ cells had been attributed to the growth-promoting and mobilizing effects of the tumor-derived GM-CSF. However, the possibility that the CD34 ุ cells of tumor bearers might have enhanced survival abilities had not been considered. The present studies showed a significant baseline level of apoptotic cells in short-term (5-day) cultures of normal CD34 ุ cells containing GM-CSF plus stem cell factor (SCF), and a markedly greater level of apoptosis in cytokine-deficient cultures. In contrast, CD34 ุ cells from tumor bearers did not undergo such levels of apoptosis, even in the absence of cytokines. This resistance to apoptosis could be conferred to normal CD34 ุ cells by culture with LLC-conditioned medium. Studies to elucidate possible mechanisms for the resistance to apoptosis by tumor-exposed CD34 ุ cells showed increased levels of the pro-life gene product bcl-2. Finally, the resistance of tumorexposed CD34 ุ cells to ligation of the Fas receptor, a known apoptotic trigger in hematopoietic cells, was compared with that of control CD34 ุ cultures. Whereas approximately half of the normal CD34 ุ cells underwent apoptosis in response to Fas ligation, the tumor-exposed CD34 ุ cells resisted apoptosis, even though their surface Fas expression was greater than that of normal CD34 ุ cells. Thus, our results show that the increased level of CD34 ุ cells in tumor bearers is due not only to an increased growth and mobilization of CD34 ุ cells as previously thought, but also may be due to an increased resistance to apoptosis that is conferred by tumorderived products and is associated with increased expression of bcl-2.