Role of Prostate apoptosis response-4 tumor suppressor in the survival and growth of Chronic Lymphocytic Leukemia

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Abstract Chronic Lymphocytic Leukemia (CLL), the most common adult leukemia in the western world, is characterized by accumulation of clonally expanded CD5 + CD19 + B lymphocytes in blood and secondary lymphoid organs with impaired apoptotic mechanisms. Prostate apoptosis response-4 (Par-4) is a pro-apoptotic tumor suppressor protein, which is silenced by promoter methylation in more than 30% of all cancers. It is also secreted and induces apoptosis selectively in many types of cancer cells but not in normal cells. Here we characterized the role of Par-4 in CLL cells using a murine model. The Eμ-Tcl1 mouse serves as an excellent model to study CLL as they develop a CLL like disease by 9–13 months of age, due to B cell specific over-expression of the oncogene, T cell Leukemia 1 (Tcl1). Adoptive transfer of primary CD5 + CD19 + CLL cells from the Eμ-Tcl1 CLL mice into recipient syngeneic mice leads to the development of a CLL like disease within 3–5 weeks of transfer. Surprisingly Eμ-Tcl1 CLL cells constitutively express more Par-4 than normal B-1 or B-2 cells in mice. These CLL cells also secrete Par-4 which is functional in being cytotoxic to prostate cancer cells. We showed that Eμ-Tcl1 CLL cells have constitutively active B-cell receptor signaling and that inhibition of BCR signaling causes a decrease in Par-4 expression and increases apoptosis. Interestingly, we have found that shRNA mediated knockdown of Par-4 in human CLL cell lines, results in their reduced growth. These results suggest that intrinsic Par-4 may play a pro-survival rather than pro-apoptotic role in CLL. We are currently investigating the mechanisms underlying this novel role of Par-4 and regulation of its expression in CLL cells using CRISPR system to knockout Lyn and Btk in CLL cells.

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