Role of BCL-2 and cell cycle regulatory proteins for corticosensitivity assessment in childhood acute lymphoblastic leukaemia

Results of treatment in childhood acute lymphoblastic leukaemia (ALL) remai n unsatisfactory because relapses occur even after high-dose chemotherapy. Corticosensitivity is used in numerous therapeutic trials as a prognostic f actor for treatment choice. The aim of this study was to evaluate the role of cell cycle regulatory protein expression before and during the first 48 h of corticotherapy for predicting corticosensitivity. Fifty-two children p resenting with ALL were studied at diagnosis and during the first 48 h of t reatment for cell proliferation and apoptosis level by measurement of DNA c ontent, and for expression of several cell proliferation regulatory protein s by means of Western blot. Glucocorticoids induced a significant decrease in the percentage of cells in S-phase and in CDK1, CDK4 and CDK6 expression and an increase in the percentage of cells in subG1 peak. Two criteria for corticosensitivity were used: (i) the number of blast cells after 7 d of t reatment with a threshold at 1 x 10(9)/l (usual criterion), (ii) the J8/J1 blast cell ratio, which is independent from initial leucocytosis. Bcl-2 exp ression at diagnosis was the best predictive variable for the usual cortico sensitivity criterion in B- and T-cell ALL. For the second criterion, in B- cell ALL, p21(waf1) expression at diagnosis was the sole (albeit poorly) pr edictive variable, whereas bcl-2 remained of high interest in T-cell ALL. I nterestingly, these proteins, bcl-2 and p21(waf1), are associated with prol onged cell lifespan and their increased expression is often linked to poor response to cytotoxic drugs. Such preliminary results call for subsequent s tudies on large independent sets of T-cell and B-cell lineage ALL in order to confirm the J8/J1 blast cell ratio value as well as the role of bcl-2 an d p21(waf1) expression in predicting corticosensitivity.