B cell malignancies such as non-Hodgkin’s Lymphoma have a probability of affecting 1 in 43 people in the United States, contributing to 7% of all cancer related deaths. The most aggressive forms of non-Hodgkin’s Lymphomas, which include Chronic Lymphocytic Leukemia (CLL), express elevated levels of T cell leukemia 1 (Tcl1), an oncogene that promotes cell survival. CLL is characterized by clonally expanded population of CD5+CD19+ B lymphocytes with impaired apoptotic mechanisms. The Eµ-Tcl1 mouse, serves as an excellent model for the development of CLL due to Tcl1 overexpression in B cells through the Ig VH promoter and Eµ enhancer. In these CLL cells the B-cell receptor (BCR) signaling pathway is activated as shown by constitutive tyrosine phosphorylation of the Src Family Kinases (SFK) and total expression of Lyn, compared to normal B cells. Treatment of B-CLL cells with dasatinib, an SFK inhibitor, results in decreased proliferation and cell death, a decrease in Tcl1, and surprisingly, a decrease in prostate apoptosis response-4 (Par-4), a pro-apoptotic protein. Knockdown of Lyn with shRNA in B-lymphoma cells, also reduced Par-4 suggesting a specific role of Lyn in Par-4 regulation. Par-4 was also downregulated after inhibition of other non-receptor tyrosine kinases such as Syk and Btk involved in BCR signaling. Presently, we are determining the importance of Par-4 in the growth of B-CLL and the mechanism of novel regulation of Par-4 and Tcl1 through BCR signaling.