Platinum-Based Compounds Induce Expression of p73 and Restores Drug- Sensitivity in p53 Dysfunctional Chronic Lymphocytic Leukemia (CLL) Cells.

Chronic lymphocytic leukemia (CLL) cells can lose function of P53 and acquire resistance to standard chemotherapy. We found that expression P73, a member of the P53 family, could be induced in CLL cells following CD40-ligation via a c-abl dependent pathway. Induced expression of P73 was associated with re-acquired sensitivity to drugs commonly used treat this disease, such as Fludarabine monophosphate. Similar effects also were noted for CLL cells transduced with an adenovirus vector encoding P73¹. Prior studies found that P73 also can be induced in breast and colon cancer cell lines following treatment with platinum-based compounds, potentially accounting for the activity of this class of drugs. We hypothesized that treatment of CLL cells with such compound also could induce P73 and that such induced expression also might be associated with re-acquired sensitivity of P53-deficient CLL cells to standard anti-cancer drugs. We studied the mechanisms and effects of platinum-based compounds on CLL cells lacking functional p53. Studies were done with both the p3 dysfunctional pro-lymphocytic celline MEC-1 and with primary CLL cells that lacked functional P53. Treatment of MEC-1 cells with cisplatinum or oxaliplatin induced nuclear translocation of c-Abl in several hours, which was subsequently followed by expression of P73, and then its putative target genes, encoding Bid, p21 and Fas (CD95). Platinum-induced expression of these P73-target genes could be inhibited by co-treatment of the cells with the c-Abl inhibitor imatinib. Cisplatinum treatment of MEC-1 cells resulted in cell cycle arrest. Furthermore, cis-platinum treatment of MEC-1 cells or P53-deficient CLL cells synergized with Fas-mediated apoptosis, and importantly resulted in acquired sensitivity to the drug fludarabine monophosphate in vitro, apparently via a c-Abl dependent pathway. Purified p53 dysfunctional CLL cells obtained before and after 24 and 48 hrs of in vivo cisplatinum treatment revealed de novo expression of both P73 and Bid, illustrating induction of P73 at therapeutic dosages of cisplatin. This study indicates that platinum treatment of CLL cells induces c-Abl dependent expression of P73, which can enhance the sensitivity of P53-deficient CLL cells to drugs such as fludarabine monophosphate. These results provide additional incentive to investigate the activity of platinum-based chemotherapy regimens in patients with refractory disease who have CLL cells lacking functional P53, which currently are ongoing in Europe and the United States.