Project Summary/Abstract Peripheral T-cell lymphomas (PTCLs) represent a heterogeneous and poorly understood pathological group of non-Hodgkin lymphomas associated with poor prognosis. Despite major progress in recent years in the identification of genomic drivers in PTCL, understanding their mechanisms of transformation and identifying therapeutic targets remain a high priority in the field. Recently we have identified novel genetic alterations in the VAV1 oncogene in PTCL using a combination of RNAseq analysis and targeted sequencing of candidate genes. Most VAV1 genomic alterations are fusions and small intragenic deletions affecting the C-terminal domain of the protein. Our central hypothesis is that the VAV1 alterations lead to increase activation of signaling pathways downstream of VAV1 and act as oncogenic drivers of PTCL. Our preliminary results demonstrate that expression of the recurrent Vav1-myo1f fusion induces lymphomas that recapitulate the histology and molecular pathology of high-risk PTCL. The goals of this project are to characterize the mechanisms by which VAV1-MYO1F fusion promotes lymphomagenesis in vivo and to explore emerging specific therapeutic vulnerabilities in PTCL preclinical models.