TYK2 Fusions in Lymphoma

PROJECT SUMMARY Malignant lymphomas are a leading cause of cancer death ranking 6th among malignancies resulting in mortality. Among these, mature T-cell lymphomas often exhibit an aggressive clinical course and their pathogenesis is poorly understood. ALK-negative anaplastic large cell lymphoma (ALK-negative ALCL) represents a poorly understood category of mature T-cell lymphomas. Unlike other hematopoietic malignancies, recurrent genetic alterations that have been exploited as rational therapeutic targets have not been described in these tumors. We discovered for the first time, recurrent translocations targeting the intracellular tyrosine kinase TYK2 in ALK- negative ALCL. In this regard, we identified a gene fusion juxtaposing the nucleophosmin (NPM1) gene (5q35) to the TYK2 gene (19p13). NPM1 is a nucleolar phosphoprotein involved in several oncogenic gene fusions and mutations in cancers. Notably, TYK2 was the first member of the Janus activating kinase (JAK) family described and propagates physiologic cytokine-driven signals and is critical for T-cell proliferation and differentiation. The signaling networks by which the NPM1::TYK2 fusion promotes lymphomagenesis are unknown. Based on our preliminary data, it is our central hypothesis that NPM1::TYK2 is an oncogenic driver that promotes the development of TCL, and that the kinase activity of NPM1::TYK2 is required for its oncogenicity. Our preliminary results demonstrate that expression of the recurrent NPM1::TYK2 fusion in conditional transgenic mice induces lymphomas that recapitulate the morphologic and genetic features of TCL, specifically ALCL. Thus, the main goal of this proposal is to investigate the in vivo oncogenicity of NPM1::TYK2 and the pathways of NPM1::TYK2- induced lymphomagenesis. The overall impact of this proposal is to advance understanding of the mechanisms by which oncogenic TYK2 causes lymphoma and identify currently unknown downstream signaling modules which may serve as vulnerability targets for novel precision therapy for oncogenic TYK2-driven cancers.