THE BAX-ALPHA BCL-2 RATIO MODULATES THE RESPONSE TO DEXAMETHASONE IN LEUKEMIC-CELLS AND IS HIGHLY VARIABLE IN CHILDHOOD ACUTE-LEUKEMIA/

Bcl-2 over-expression has been shown to inhibit apoptosis induced by a variety of stimuli, whereas a predominance of Bax alpha to Bcl-2 acce lerates apoptosis upon apoptotic stimuli. We sought to study the relev ance of these apoptotic regulating gene products in leukaemia. In a pa nel of leukaemia and lymphoma cell lines (HL60, DoHH2, CEM C7, LI210 a nd S49), the Bax alpha-to-Bcl-2 ratio as assessed by Western-blot anal ysis correlated with sensitivity to dexamethasone treatment. In additi on, in HAbax alpha-transfected CEM C7 clones, a similar correlation wa s found for dexamethasone and thapsigargin sensitivity. In bone-marrow aspirates from patients with childhood acute lymphoblastic or myelocy tic leukaemia (ALL, n = 48; AML, n = 8), the Bcl-2 and Bax alpha level s were highly variable, but well within the range found in the Bax alp ha transfectants and in the established cell lines. Bcl-2 levels were lower in T- than in B-lineage ALL, which could be ascribed to simultan eous inverse relation between Bcl-2 and WBC. By contrast, Bax alpha:Bc l-2 was independent of any presenting feature and was largely dependen t on Bax alpha levels. Results suggest that Bax alpha:Bcl-2, rather th an Bcl-2 alone is important for the survival of drug-induced apoptosis in leukemic cell lines and ALL. (C) 1997 Wiley-Liss, Inc.