Analysis of the mechanism for suppression of childhood leukemia via ARF-p53 pathway

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ARF, a tumor suppressor gene product, is seemed to protect cells from leukemic transformation via p53-dependent pathway. In this study, we performed the analysis of lymphocyte surface markers on ARF-null lymphocytes and examined hematopoietic cell colony formation from bone marrow cells cultured in the presence of several combinations of the cytokines. However, ARF-null cells did not possess specific surface makers and growth advantage compared to wild-type cells. ARF sensitizes cells to apoptosis in the presence of appropriate collateral signals. Therefore, we analyzed the mechanism of ARF-dependent apoptosis to study the role of ARF on tumor suppression. We demonstrated that ARF induces mitochondria-dependent apoptosis in p53 wild-type cells. We also found that ARF evokes cytochrome c release from mitochondria, decreases mitochondrial membrane potential and activates pro-caspase-9 to induce apoptosis. This pro-apoptotic cellular modulation appeared to be brought about by upregulation of the ratio of two sets of pro-apoptotic/anti-apoptotic initochondrial proteins, Bax/Bcl-2 and Bim/Bcl-2. Whereas downregulation of Bcl-2 by ARF was via a p53-dependent pathway, Bax and Bim upregulation was induced by serum starvation.