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

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.; Rabadan, R.; Ferrando, A. A.; Palomero, T.

doi:10.1073/pnas.1608839114

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.

Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas / 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., Rabadan, R., et al.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 114:4(2017), pp. 764-769. [10.1073/pnas.1608839114]