The Par-4 tumor suppressor protein in TCL1-induced leukemogenesis

Prostate apoptosis response 4 (Par-4) is a pleiotropic tumor suppressor protein that is downregulated in numerous solid tumors to evade its pro-apoptotic and cytostatic effects. Par-4 is thought to respond to dysregulation of various signaling pathways during oncogenic transformation by promoting expression of pro-apoptotic proteins and inhibiting transcriptions factors vital to proliferation. It has been shown to be a faithful indicator of response to chemotherapy in breast cancer and is being explored in other cancers as a factor in response to multiple classes of therapeutics. Despite this, its role in hematological malignancies has been little described. Studies in leukemia have shown that Par-4 expression levels correlate with known prognostic indicators and may factor into treatment response and disease progression. These reports also indicate that dysregulation of the pathway differs between different forms of leukemia, and the significance of Par-4 activity may vary between chronic, acute, lymphoid, and myeloid forms of the disease. Par-4 expression levels are also variable within different forms of leukemia and correlate with incidence of other genetic lesions that impact prognosis and treatment outcomes. Follow-up, in vitro studies have provided some mechanistic insight into how Par-4 functions in different forms of leukemia and suggest relevance to the apoptotic response of leukemia cells to therapeutics. Additionally, animal models of chronic lymphocytic leukemia (CLL) have revealed that extrinsic and intrinsic Par-4-mediated effects may both play a role in leukemogenesis, adding more complexity to the collective understanding of this protein's role in hematologic disease. Given the relevance of Par-4 activity in treatment of solid tumors, further exploration of this pathway n heme malignancies may be clinically relevant. This chapter contains an analysis of literature regarding Par-4 in leukemia, recently published data suggesting a role for leukemogenesis in CLL, and future prospects for utilizing Par-4 to therapeutic benefit in patients.