RESISTANCE TO APOPTOSIS CORRELATES WITH A HIGHLY PROLIFERATIVE PHENOTYPE AND LOSS OF FAS AND CPP32 (CASPASE-3) EXPRESSION IN HUMAN LEUKEMIA-CELLS

Apoptosis induced by effector cells of the immune system or by cytotox ic drugs is a main mechanism mediating the prevention or elimination o f tumoral cells. For instance, the human T-cell leukemia Jurkat is sen sitive to Fas-induced apoptosis and to activation-induced cell death ( AICD), and the promonocytic leukemia U937 is sensitive to Fas- and TNF -induced apoptosis. In this work, we have analyzed the mechanisms of r esistance to physiological or pharmacological apoptosis in human leuke mia by generating highly proliferative (hp) sub-lines derived from jur kat and U937 cells. These hp sub-lines were resistant to Fas- and TNF- induced apoptosis, as well as to AICD. This was due to the complete lo ss of Fas and TNFR surface expression and, in the case of jurkat-deriv ed sub-lines, also of CD3, CD2 and CD59 molecules. The sub-lines also completely lacked the expression of the apoptotic protease CPP32, pres ent in parental cells. Moreover, these sub lines were no longer sensit ive to doxorubicin-induced apoptosis, which was efficiently blocked by the general caspase inhibitor Z-VAD-fmk in the parental cell lines. T hese data suggest a molecular mechanism for the development of resista nce of leukemic cells to physiological and pharmacological apoptosis i nducers, giving rise to highly proliferative tumoral phenotypes. These results also indicate that pas and CPP32 could be useful prognostic m arkers for the progression and/or therapy outcome of human leukemias. (C) 1998 Wiley-Liss, Inc.