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
Beasley, Samantha M; Plikus, Maksim V; Spitale, Robert C et al. (2015) The emerging functions of regulatory RNA species in skin biology. Exp Dermatol 24:827-8 |
Hamdorf, Matthias; Idica, Adam; Zisoulis, Dimitrios G et al. (2015) miR-128 represses L1 retrotransposition by binding directly to L1 RNA. Nat Struct Mol Biol 22:824-31 |
Miletic, Ana V; Anzelon-Mills, Amy N; Mills, David M et al. (2010) Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases. J Exp Med 207:2407-20 |
Pedersen, Irene M; Otero, Dennis; Kao, Elaine et al. (2009) Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas. EMBO Mol Med 1:288-95 |