Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas.
Abate F, da Silva-Almeida AC, Zairis S, Robles-Valero J, Couronne L, Khiabanian H, Quinn SA, Kim MY, Laginestra MA, Kim C, Fiore D, Bhagat G, Piris MA, Campo E, Lossos IS, Bernard OA, Inghirami G, Pileri S, Bustelo XR, Rabadan R, Ferrando AA, Palomero T.
Source :
Proc Natl Acad Sci U S A
2017 Jan 24
Pmid / DOI:
28062691
Abstract
Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of non-Hodgkin lymphomas frequently associated with poor prognosis and for which genetic mechanisms of transformation remain incompletely understood. Using RNA sequencing and targeted sequencing, here we identify a recurrent in-frame deletion (VAV1 Δ778-786) generated by a focal deletion-driven alternative splicing mechanism as well as novel VAV1 gene fusions (VAV1-THAP4, VAV1-MYO1F, and VAV1-S100A7) in PTCL. Mechanistically these genetic lesions result in increased activation of VAV1 catalytic-dependent (MAPK, JNK) and non-catalytic-dependent (nuclear factor of activated T cells, NFAT) VAV1 effector pathways. These results support a driver oncogenic role for VAV1 signaling in the pathogenesis of PTCL.