Role of Par-4 in B-cell hematological malignancies

Prostate apoptosis response-4 (Par-4) was identified as a tumor suppressor protein that is silenced by promoter methylation in various cancers and has been shown to induce apoptosis selectively in cancer cells but not in normal cells. Par-4 interacts with a variety of partners in cells to mediate various cellular responses and appears to have a pro-apoptotic role in non-hematological tumors. Here, we summarize the literature on the role of Par-4 in hematological cells that is in contrast to its classic pro-apoptotic role. Par-4 is expressed basally in various hematopoietic cells and malignancies at the mRNA and protein level, but is predominant in the early stages of B-cell maturation and specifically in chronic lymphocytic leukemia (CLL). CLL B cells express higher levels of Par-4 than normal B-cell subsets and constitutively active B-cell receptor signaling (BCR) maintains high Par-4 levels in these cells, suggesting a novel regulation of Par-4 through BCR signaling. CLL cell growth is dependent on BCR signaling-mediated Par-4 expression, which is in part due to downregulation of p21 by Par-4. Bcl2 and NF-κB pathways cause differential regulation of apoptotic genes in contrast to non-hematological cancers, and Par-4 may also play a significant role in tumor microenvironment. Thus, Par-4 appears to have unique roles in hematological malignancies.