Good early treatment response in childhood acute lymphoblastic leukemia is associated with Bax nuclear accumulation and PARP cleavage
Tomasz Urasinski, Elzbieta Urasinska, Jerzy Grabarek, Janusz Fydryk, Wenancjusz Domagala
Med Sci Monit 2009; 15(6): CR294-301
Available online: 2009-05-29
Bax activation and intracellular redistribution as well as its prognostic significance during steroid-induced apoptosis of leukemic cells in childhood acute lymphoblastic leukemia (ALL) remain a matter of controversy. The purpose of this study was to assess time-resolved changes in Bax activation and its intracellular distribution as well as the percentage of apoptotic cells evaluated by PARP cleavage in response to prednisone treatment in childhood ALL.
Material and Method: The study comprised 43 children with de novo ALL. Bax activation and PARP cleavage were measured by laser scanning cytometry in peripheral blood mononuclear cells collected prior to and 6 and 12 hours after prednisone administration.
Results: The mean pretreatment proportion of p89 PARP-positive cells was 3.5%. Six and twelf hours after prednisone administration it increased significantly (p<0.01) only in the group of good treatment responders. A significant rise (p<0.05) in cytoplasmic Bax expression was seen in the good responders as early as 6 hours after prednisone administration followed by a significant rise in Bax nuclear expression after 12 hours. At the same time points the mean percentage of apoptotic cells as well as Bax expression in the cytoplasm and nucleus remained unchanged in the group of poor responders.
Conclusions: Increased Bax nuclear accumulation (and possibly also aggregation) together with increased PARP cleavage observed within 12 hours after prednisone oral administration were associated with and may predict good outcome in children with newly diagnosed ALL.
Keywords: Prednisone - therapeutic use, Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology, Poly(ADP-ribose) Polymerases - metabolism, Leukocytes, Mononuclear - metabolism, Fluorescein-5-isothiocyanate, Fluorescence, Child, Child, Preschool, Cell Nucleus - metabolism, Adolescent, bcl-2-Associated X Protein - metabolism