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1731 Role of Prostate Apoptosis Response-4 Tumor Suppressor in the Survival and Growth of Chronic Lymphocytic Leukemia

CLL: Biology and Pathophysiology, excluding Therapy
Program: Oral and Poster Abstracts
Session: 641. CLL: Biology and Pathophysiology, excluding Therapy: Poster I
Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)

Sunil K Nooti, Ph.D.1,2*, Mary K McKenna, B.S.1*, Frank W Frissora, M.S.3*, Beth W Gachuki, M.S.1*, Sara S Alhakeem, M.S.1*, Joseph T Greene, M.S.3*, Natarajan Muthusamy, DVM, Ph.D.3,4, Vivek M Rangnekar, Ph.D.1,2* and Subbarao Bondada, Ph.D.1*

1Microbiology, Immunology, and Molecular Genetics and Markey Cancer Center, University of Kentucky, Lexington, KY
2Department of Radiation Medicine, University of Kentucky, Lexington, KY
3Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
4Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, OH

Chronic Lymphocytic Leukemia (CLL) is characterized by accumulation of clonally expanded population of CD5+ CD19+ B lymphocytes in peripheral blood and secondary lymphoid organs, with a majority of circulating cells in a non-dividing resting stage. However CLL is no longer considered a static disease that results from simple accumulation of long-lived lymphocytes, but rather, is a dynamic process with a birth rate of about 0.1-2% of the entire CLL clone per day. The Eµ-Tcl1 mouse serves as an excellent model for the development of CLL as they develop a CLL like disease by 9-13 months of age, due to overexpression of the oncogene, T cell Leukemia 1 (Tcl1), in B cells through the Ig VH promoter and Eµ enhancer (Bichi et al. PNAS. 2002). In an adoptive transfer model, intravenous or intraperitoneal injection of primary CD5+CD19+ CLL cells from the Eµ-Tcl1 CLL mouse into recipient syngeneic mice leads to development of a CLL like disease within 3-5 weeks of transfer. We have characterized the growth of CLL cells in these mice by periodic submandibular bleeding, ultrasonography of spleen and flow cytometry. We find that Eµ-Tcl1 CLL cells express more Prostate apoptosis response-4 (Par-4), a pro-apoptotic tumor suppressor protein, than normal B-1 or B-2 cells in mice. Par-4 is silenced by promoter methylation in more than 30% of all cancers. Par-4 has been shown to be secreted and to induce apoptosis selectively in various types of cancer cells but not in normal cells. Although we find that Eµ-Tcl1 CLL cells constitutively secrete Par-4, they are resistant to Par-4 mediated apoptosis. We show that CLL cells have constitutively active B-cell receptor signaling and that inhibition of BCR signaling with FDA approved drugs (i.e. Dasatinib, Ibrutinib, and Fostamatinib) causes a decrease in Par-4 protein and mRNA levels and increases apoptosis. Interestingly, systemic Par-4 appears to inhibit CLL growth in vivo, since adoptively transferred Eµ-Tcl1 CLL cells grew better in Par-4 null mice, despite excellent Par-4 expression and secretion by the transferred cells. Thus there were three times more CLL cells in the bone marrow and twice as many in the spleens of Par-4 null mice compared to their wild type counterparts. We conclude that even though Par-4 is pro-apoptotic in the CLL microenvironment, intracellular Par-4 is either rendered inactive or is potentially pro-survival in Eµ-Tcl1 CLL cells. (Supported in part by NIH grants)

Disclosures: No relevant conflicts of interest to declare.

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