VAV1 Activating Mutations and Translocations in Peripheral T-Cell Lymphomas

Peripheral T-cell lymphomas (PTCL) are malignant and highly aggressive hematologic tumors arising from mature post thymic T-cells. The diagnosis of PTCL includes diverse lymphoma subgroups, altogether accounting for about 15% of all non-Hodgkin lymphomas. Despite much effort in developing reliable diagnostic markers, the diagnosis of PTCLs is challenging and 20-30% of cases are diagnosed as PTCL-NOS (not otherwise specified). This heterogeneous and poorly defined group of lymphomas is frequently characterized by chemotherapy resistance and a very poor prognosis. Here we report the presence of recurrent driver activating genetic alterations in the VAV1 gene in PTCL, NOS. RNA-seq analysis of a comprehensive series of 154 PTCLs and targeted sequencing identified VAV1 gene fusions with different partners including VAV1-THAP4, VAV1-MYO1F and VAV1-S100A7. In all cases the resulting oncoproteins lack the C-terminal SH3 domain of VAV1, a motif implicated in the negative regulation of VAV1 signaling, leading to increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (NFAT) VAV1 effector pathways. In addition, and most notably, we also identified focal microdeletions at the VAV1 intron 25-exon 26 boundary, which result in the activation of an alternative intraexonic splice acceptor site and the consequent expression of mis-splicing-driven mutant transcripts harboring a recurrent VAV1 Δ778-786 in-frame deletion. Mechanistically, the VAV1 Δ778-786 mutation removes 9 amino acids proximal to the C-terminal VAV1 SH3 domain and induces in increased VAV1 activation and signaling in biochemical assays. In all, these results support a driver role for oncogenic VAV1 signaling in T-cell transformation of major importance for the design of targeted therapies for the treatment of PTCL, NOS.