NPM-ALK & CD30 Signaling in Anaplastic Cell Lymphoma

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DESCRIPTION (provided by applicant): Anaplastic Large Cell Lymphoma (ALCL) comprises 10% of all non-Hodgkin's lymphoma. ALCL are uniformly CD30 (+) and 50-60% of ALCL are characterized by the t (2;5) translocation which produces a fusion protein between Nucleophosmin on chromosome 5 and Anaplastic Lymphoma Kinase (ALK) on chromosome 2. NPM-ALK is an oncogenic tyrosine kinase that activates multiple signal transduction pathways. A number of NPM-ALK (+) cell lines have been shown to undergo growth arrest when CD30 is activated. The goal of this proposal is to: 1) determine which signaling pathways are critical for transformation, and 2) determine how CD30 modulates NPM-ALK pathways. To accomplish these goals the applicant will: 1) Determine how NPM-ALK activates PI3K and the STATs, 2) Determine the role of PLC-?, PI3-kinase, STATs and scaffolding proteins in NPM-ALK induced lymphomagenesis in a murine bone marrow transplant model, 3) Determine the mechanism by which CD30 modulates NPM-ALK signaling pathways. These studies will provide valuable insight into the biology of NPM-ALK (+) lymphomas that may lead to new therapeutic modalities. The candidate, who completed an academic Hematology-Oncology fellowship at Beth Israel Deaconess Medical Center, is committed to a career in academic medicine with an emphasis in translational research. The proposed five-year course of study will give the candidate a broad experience in fields of immunotherapy and signal transduction leaving him prepared to make the transition to independent investigator.