Tumor proliferative compartment, multidrug resistance gene product and apoptosis regulatory p53 and bcl-2 proteins in pediatric acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most frequent childhood tumor. Although the cure rate has increased dramatically over the past few years, the molecular and cellular biology of this disease is still not fully understood. Important factors affecting prognosis include age, leucocyte count, cytogenetic abnormalities, immunophenotype and sex. However, the role of cell kinetics, tumor associated genes and drug resistance have rarely been investigated in pediatric ALL. This preliminary study looks at these aspects in this disease. Immunocytochemical analysis of the tumor suppressor protein p53, the anti apoptotic protein bcl-2, the multidrug resistance (MDR) gene product P-glycoprotein and the proliferation marker, Ki-67 were done using appropriate monoclonal antibodies. A total of 88 previously untreated children with confirmed ALL diagnosis and 40 age matched controls were included in the study. Ki-67 was expressed in 81% and P-glycoprotein in 68% of all cases. P53 expression was observed in 68% and Bcl-2 in 50% of cases. Fifty percent of all cases also showed concomitant expression of bcl-2 and p53. Since wild-type p53 is known to negatively regulate the expression of bcl-2, the co-expression of these two proteins having contrasting functions suggests that the p53 may be of a mutant variety. In addition, the expression of p53 also correlates to the presence of the multidrug gene product P-glycoprotein. Control samples were negative for all the four markers. P53, bcl-2 and P-glycoprotein can all influence chemotherapy resistance, the first two by regulating programmed cell death and the third by influencing intracellular drug levels. All patients are now being followed up to assess treatment response and to study the prognostic significance of the analyzed markers.