Angioimmunoblastic T cell lymphoma (AITL) and peripheral T cell lymphoma not-otherwise-specified (PTCL, NOS) have poor prognosis and lack actionable targets for directed therapies in most cases. Here we report the identification of FYN-TRAF3IP2 as a novel highly recurrent oncogenic gene fusion in AITL and PTCL, NOS tumors. Mechanistically, FYN-TRAF3IP2 triggers aberrant NF-κB activity by engaging TRAF6 downstream of T cell receptor signaling. Moreover, FYN-TRAF3IP2 expression in hematopoietic progenitors induces NF-κB-driven T cell transformation in mice and cooperates with loss of the Tet2 tumor suppressor in PTCL development. Therapeutically, abrogation of NF-κB signaling in FYN-TRAF3IP2-induced tumors via IκB kinase inhibitors delivers strong anti-lymphoma effects in vitro and in vivo. These results formally demonstrate an oncogenic role for FYN-TRAF3IP2 and NF-κB signaling in the pathogenesis of PTCL.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/d8-5w9r-w324 |
| Date | January 2020 |
| Creators | Kim, Christine Sheila |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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