Dysregulation of apoptosis is an important mechanism in leukemogenesis.
Caspases are
cysteine proteases that play a major role in the activation of apoptotic pathways and
chemotherapy-induced cell death. High levels of inactive, uncleaved
caspase 2 and
caspase 3 have recently been associated with poor survival in patients with
acute myelogenous leukemia. We hypothesized a similarly significant role for
caspase 2 and
caspase 3 in patients with
acute lymphoblastic leukemia. We determined levels of uncleaved
caspase 2 and
caspase 3 by quantitative Western blot analysis in peripheral blood samples of 45 adults with newly diagnosed ALL. We evaluated patient prognostic variables and
caspase levels using multivariate logistic and Cox regression models to determine their impact on complete remission rate and overall survival probability. Levels of
caspase 2 and, to a lesser degree,
caspase 3 were highly associated with
cytogenetic abnormalities, with lower levels in the diploid group (P = 0.016 and P = 0.10, respectively). No association between either
caspase level and the percentage of bone marrow blasts was found. A high level of
caspase 3 (>0.37 as determined graphically) was significantly associated with achieving complete remission (CR; P = 0.006). A multivariate logistic regression analysis including age, WBC count, percentage of peripheral and marrow blasts,
hemoglobin,
albumin,
lactate dehydrogenase,
bilirubin, and
creatinine determined that a high level of
caspase 3 was the most significant predictor of CR (P = 0.025, adjusted), with
albumin the only other significant variable (P = 0.031).
Caspase 2 levels were not associated with probability of CR. In a multivariate Cox model for survival, however, levels of
caspase 2 above 0.37 were associated with a lower survival probability than were levels below that threshold (P = 0.064). High levels of
caspase 3 may have a significant effect on achieving CR. Because of the limited power (n = 45) of our study, the significance of
caspase 2 and
caspase 3 on overall survival remains to be validated by further investigations.