CASPASE-2 AND CASPASE-3 PROTEIN-LEVELS AS PREDICTORS OF SURVIVAL IN ACUTE MYELOGENOUS LEUKEMIA

Because caspase activation is an essential step in programmed cell dea th (apoptosis) and cytotoxic drug-induced apoptosis is mediated by cas pase 2 and caspase 3, we hypothesized that caspase 2 and 3 levels pred ict clinical outcome in acute myelogenous leukemia (AML). Using quanti tative Western blot analysis, we studied the levels of nonactivated (u ncleaved) caspase 2 and 3 in peripheral blood low-density cells from 1 85 patients with newly diagnosed AML. We also measured the level of ac tivated (cleaved) caspase 3 in 41 randomly selected samples from the 1 85 patients. Finally, we analyzed the effect of caspase 2 and 3 levels and other prognostic variables on patient survival using a multivaria te Cox model. We found that median levels of nonactivated caspase 2 an d 3 were higher in AML than in normal peripheral blood cells (P < .001 and P < .02, respectively). There was no association between caspase level and either the percentage of peripheral blasts or any specific t ype of leukemia cell cytogenetic abnormalities. When the effect of eac h uncleaved caspase was considered individually, a high level of uncle aved caspase 3 (P = .04), but not of caspase 2 (P = .16), was associat ed with decreased survival. Conversely, a high level of cleaved caspas e 3 denoted improved survival and correlated with the inactivation of the DNA-repair enzyme poly(ADP-ribose) polymerase. Thus, cleaved caspa se 3 could stimulate the apoptotic cascade further, and lack of its ac tivation likely caused an accumulation of the uncleaved caspase. Altho ugh uncleaved caspase 2 level per se had no prognostic significance, t he interactive effect of high levels of both uncleaved caspase 2 and 3 denoted very poor survival (P < .001) and had the largest effect of a ll prognostic variables (P < .001; estimated relative risk, 2.49; 95% confidence interval, 1.59 to 3.90). Taken together, caspase 2 and casp ase 3 protein levels obtained at diagnosis may constitute a reliable p rognostic factor in AML. (C) 1998 by The American Society of Hematolog y.