B-cell cancers such as CLL (Chronic Lymphocytic Leukemia), FL (Follicular Lymphoma) and DLBCL (Diffuse Large B-cell Lymphoma) account for the majority of hematological malignancies in the Western World. These cancers feature a dysregulated PIS kinase pathway, which is a pivotal signaling pathway that promotes cellular proliferation and survival, and enhances adhesion and migration. PI3K is regulated by the phosphatases PTEN (phosphatase and tensin homolog deleted on chromosome ten) and SHIP (SH2 domain-containing inositol 5-phosphatase). PTEN is a known tumor suppressor and mutated in human cancer with a frequency approaching that of p53. Surprisingly, while conditional deletion in T-cells (tPTEN) results in T-cell lymphoma, deletion in B-cells (bPTEN) does not result in transformation. In this proposal, the role of PTEN and SHIP in counter-acting PI3K activity and transformation-, in B-cells-, will be addressed through the use of double conditional knock-out mice and patient specimen analysis. In addition, the signal transduction pathways involved in transformation will be characterized and findings applied to the development of potential therapeutics for lymphoma. Finally, as preliminary cDNA array analysis reveals an inverse relationship between PTEN/SHIP expression and the severity of disease, (DLBCL<FL<CLL), further genomic and proteomic analyses of human tumor specimens will be performed to determine if the loss of PTEN/SHIP can be used as a prognostic marker for survival or progression of disease. This award will provide the candidate a period of mentored research in the laboratory of Dr. Michael David, an expert in uniting the fields of signal transduction and mouse model characterization. The University of California, San Diego provides an excellent research environment with possibilities to collaborate with top researchers at nearby institutes as well as across the country. Dr. David's expertise, research collaborations, and resources will assist the candidate in the development of the skills and autonomy required to become a successful independent investigator.
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