Peripheral T-cell lymphomas (PTCL) are highly aggressive lymphoid tumors derived from post-thymic mature T-cells. Accounting for 10-15% of non-Hodgkin lymphomas of North America with increasingly more people being diagnosed with the disease, PTCL is associated with dismal prognosis of 5 year survival rate at about 30%. The scarcity of information on driver oncogenes and their contribution to the lymphomagenesis has further hindered the identification of therapeutic targets, underscoring the need to identify the elusive mechanisms of PTCL tumorigenesis. This project aims to analyze oncogenic role and mechanisms of FYN- TRAF3IP2, a novel recurrent PTCL fusion oncogene identified via RNA sequencing analyses. Fyn is a SRC family tyrosine kinase with a crucial role in T-cell receptor (TCR) signaling, while TRAF3IP2 is a signaling adaptor protein implicated in canonical NF-?B activation. FYN-TRAF3IP2 fusions are composed of the N- terminal regulatory regions of Fyn kinase and the signaling and protein-protein interaction domains of the TRAF-interacting protein 2 (TRAF3IP2) adaptor protein. Of note, TCR signaling and NF-?B activation are both important regulators of cell proliferation and survival in PTCL lymphoma. I have demonstrated that FYN- TRAF3IP2 fusions induce increase in NF-?B signaling in response to protein kinase C (PKC) activation, which endogenously follows TCR activation in T-cells. My central hypothesis is that FYN-TRAF3IP2 deregulates NF- ?B signaling in T-cell progenitors promoting activation of downstream effector pathways implicated in lymphoma transformation. Here I will formally explore the mechanisms of T-cell transformation by FYN- TRAF3IP2 in PTCLs. Specifically: (i) investigate the functional consequences of FYN-TRAF3IP2 expression in TCR signaling, cell growth, proliferation and survival in primary T-cells; (ii) identify the biochemical mechanisms mediating NF-?B activation by FYN-TRAF3IP2; and (iii) analyze the oncogenic role of FYN- TRAF3IP2 in T-cell transformation in vivo.
FYN-TRAF3IP2 is a recurrent fusion oncogene in peripheral T-cell lymphomas implicating the N-terminal region of the FYN Src kinase and the NF-?B signaling adaptor protein TRAF3IP2. Here I will analyze the oncogenic role and mechanisms of FYN-TRAF3IP2 in the pathogenesis of T-cell lymphoma using a combination of cellular, biochemical, and genetic assays in vitro and in vivo.
