Chronic lymphocytic leukemia (CLL), also known as small cell lymphoma, constitutes almost 30% of all cases of non-Hodgkin's lymphoma. It is the most common adult leukemia. Despite advances in chemotherapy, treatment options for CLL patients are limited with only a modest efficacy, especially for patients with unmutated types of B cell receptors (BCR), del (17p13.1) and p53 mutations. Tcl-1, an oncogene, initially found to be translocated in T-cell leukemias, has been found to be expressed at higher levels in CLL phenotypes that are classified as aggressive. A mouse model for CLL has been generated by expressing the Tcl-1 oncogene in B cells using immunoglobulin promoter and the E? enhancer. These mice reproducibly develop CLL in 13-18 months and have been shown to be excellent models for human CLL. Par-4 is a pro-apoptotic tumor suppressor, discovered by us, that induces apoptosis in cancer but not normal cells using both the Fas pathway and by inhibiting NF-?B. We made four novel observations. First, the B-cell receptor signaling pathway is active both in the human CLL cells and in the E?-Tcl-1 mouse model of CLL as reflected by constitutive activation of Src family protein tyrosine kinases (SFK). Second, we discovered that expression of Tcl1 is down regulated upon inhibition of SFK suggesting a role for BCR signaling in Tcl1 expression. Third we found that expression of Par-4 is down-regulated in E?-Tcl1 CLL cells compared to normal mice, while its expression has been found to be variable in human CLL cells. Fourth we discovered that E?-Tcl1 cells are killed by soluble Par-4 and SAC, a specific domain of Par-4 that is cytotoxic only to tumor cells. Based on these observations we hypothesize that a balance between Tcl1 and Par-4 regulated by BCR signaling decides the fate of CLL cells between survival and death. We have three specific aims.
Aim 1 will determine the importance of BCR signaling and the role of specific SFKs in the regulation of Tcl-1 and Par-4 expression using the E?-Tcl-1 mouse model of CLL.
Aim 2 will investigate the importance of Par-4 overexpression for CLL development using a newly generated inducible Par-4 transgenic mice mouse model and the E?-Tcl-1 mice.
Aim 2 will involve preclinical studies to test the efficacy of extracellular Par-4 and SAC to inhibit CLL growth in the E?-Tcl-1 mouse model. The relative importance of Tcl-1 and Par-4 will be studied in Aim 3 with primary CLL cells from patients, thus translating the basic research findings in Aims 1 and 2 to clinical samples. The collaboration between UK and OSU provides us an opportunity to integrate the basic science and pre-clinical findings from the first two Aims with studies in Aim 3 using patient derived CLL cells. The exciting aspect of these studies is the possibility that soluble Par-4 or SAC can be developed into a treatment strategy for CLL cells either in isolation or in combination with SFK inhibitors or other targets that are currently being investigated in our laboratories.

Public Health Relevance

The efficacy of existing therapeutic modalities for Chronic lymphocytic leukemias, which affect mainly older adults is not high and new therapies for this disease are not yet available. The proposed studies will focus on two novel molecules Tcl-1 and Par-4 that have antagonistic roles in survival of CLL cells and may provide new avenues that can be developed into therapeutic strategies.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Howcroft, Thomas K
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University of Kentucky
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