EXPRESSION AND REGULATION OF BCL-2, BCL-XL, AND BAX CORRELATE WITH P53 STATUS AND SENSITIVITY TO APOPTOSIS IN CHILDHOOD ACUTE LYMPHOBLASTIC-LEUKEMIA

Bcl-2 anal its homologue, Bcl-xl, encode membrane-associated proteins that protect neoplastic cells from DNA damage-induced apoptosis, where as Bax is a Bcl-2 antagonist that promotes cell death. In the present study, we examined the expression and regulation of these genes at bot h the mRNA and protein level in 22 pediatric acute lymphoblastic leuke mia (ALL) cell lines, as well as their sensitivity to apoptosis after exposure to ionizing radiation (IR). Eleven of 22 lines expressed wild -type (wt) p53, 4 expressed mutant p53, and 7 did not express p53 (p53 -null). Nine of 22 (41%) lines expressed Bcl-2; of these, 8 were wt-p5 3(+) and 7 expressed mutant p53. Bcl-2 was not expressed in any p53-nu ll lines. In contrast, all 22 lines were positive far Bcl-xl and Bax, although expression level varied. Treatment with IR (10 Gy) induced bo th downregulation of Bcl-2 and upregulation of Bax at 2 to 5 hours pos t-IR in 5 of 8 (63%) wt-p53(+) lines, reading to apoptosis. Conversely , lines that failed to both downregulate Bcl-2 and upregulate Bax afte r IR were resistant to apoptosis. Although levels of Bcl-xl expression varied among the 22 lines, high levels of Bcl-xl were observed in 5 o f 7 (71%) p53-lines. There were no obvious changes in the expression o f Bcl-xl in these lines after IR. However, among the p53-null lines, r esistance to IR was observed only in those expressing high levels of B cl-xl. These results suggest that expression of Bcl-2 but not Bcl-xl i s p53-dependent and that IR-induced downregulation of Bcl-2 and upregu lation of Bax occur in most wt-p53(+) lines and are associated with ra diosensitivity. Furthermore, high-level expression of Bcl-xl occurs pr edominantly in p53-null lines and is associated with resistance to IR- induced apoptosis in these lines, indicating differential expression a nd regulation of Bcl-2 and Bcl-xl in pediatric ALL. (C) 1997 by The Am erican Society of Hematology.