Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas

作者：Abate Francesco; da Silva Almeida Ana C; Zairis Sakellarios; Robles Valero Javier; Couronne Lucile; Khiabanian Hossein; Quinn S Aidan; Kim Mi Yeon; Laginestra Maria Antonella; Kim Christine; Fiore Danilo; Bhagat Govind; Piris Miguel Angel; Campo Elias; Lossos Izidore S; Bernard Olivier A; Inghirami Giorgio; Pileri Stefano; Bustelo Xose R; Rabadan Raul; Ferrando Adolfo A; Palomero Teresa

来源：Proceedings of the National Academy of Sciences, 2017, 114(4): 764-769.

DOI：10.1073/pnas.1608839114

• peripheral T-cell lymphoma
• VAV1
• mutation
• gene fusion

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 Delta 778-786) 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.

• 出版日期2017-1-24