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

Francesco Abate, Ana C. Da Silva-Almeida, Sakellarios Zairis, Javier Robles-Valero, Lucile Couronne, Hossein Khiabanian, S. Aidan Quinn, Mi Yeon Kim, Maria Antonella Laginestra, Christine Kim, Danilo Fiore, Govind Bhagat, Miguel Angel Piris, Elias Campo, Izidore S. Lossos, Olivier A. Bernard, Giorgio Inghirami, Stefano Pileri, Xosé R. Bustelo, Raul RabadanAdolfo A. Ferrando, Teresa Palomero

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)764-769
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number4
DOIs
Publication statusPublished - Jan 24 2017

Keywords

  • Gene fusion
  • Mutation
  • Peripheral T-cell lymphoma
  • VAV1

ASJC Scopus subject areas

  • General

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  • Cite this

    Abate, F., Da Silva-Almeida, A. C., Zairis, S., Robles-Valero, J., Couronne, L., Khiabanian, H., Quinn, S. A., Kim, M. Y., Laginestra, M. A., Kim, C., Fiore, D., Bhagat, G., Piris, M. A., Campo, E., Lossos, I. S., Bernard, O. A., Inghirami, G., Pileri, S., Bustelo, X. R., ... Palomero, T. (2017). Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas. Proceedings of the National Academy of Sciences of the United States of America, 114(4), 764-769. https://doi.org/10.1073/pnas.1608839114