title: Activating mutations and translocations in the guanine exchange factor VAV1 in peripheral T-cell lymphomas.
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.
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Francesco
authors.initials: F
authors.lastname: Abate
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Ana C
authors.initials: AC
authors.lastname: da Silva-Almeida
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Sakellarios
authors.initials: S
authors.lastname: Zairis
authors.affiliation: Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, 37007 Salamanca, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Robles-Valero
authors.affiliation: Department of Adult Hematology, Necker Hospital, 75015 Paris, France.|INSERM UMR163, Centre National de la Recherche Scientifique Équipe de Recherche Labellisée 8254, Institut Imagine, 75015 Paris, France.|Paris Descartes University, 75006 Paris, France.
authors.forename: Lucile
authors.initials: L
authors.lastname: Couronne
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: S Aidan
authors.initials: SA
authors.lastname: Quinn
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.affiliation: Hemopathology Unit, European Institute of Oncology, 20139 Milan, Italy.
authors.forename: Maria Antonella
authors.initials: MA
authors.lastname: Laginestra
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032.
authors.forename: Christine
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Danilo
authors.initials: D
authors.lastname: Fiore
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Instituto de Formación e Investigación, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain.
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Piris
authors.affiliation: Department of Pathology, Hospital Clinic, 08036 Barcelona, Spain.
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.affiliation: Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL 33136.|Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33101.
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
authors.affiliation: INSERM U1170, 94805 Villejuif, France.|Université Paris-Sud, 91405 Orsay, France.|Gustave Roussy, 94805 Villejuif, France.
authors.forename: Olivier A
authors.initials: OA
authors.lastname: Bernard
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Inghirami
authors.affiliation: Hemopathology Unit, European Institute of Oncology, 20139 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pileri
authors.affiliation: Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, 37007 Salamanca, Spain.|Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Spain.
authors.forename: Xosé R
authors.initials: XR
authors.lastname: Bustelo
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, NY 10032; rr2579@cumc.columbia.edu af2196@columbia.edu tp2151@columbia.edu.|Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032; rr2579@cumc.columbia.edu af2196@columbia.edu tp2151@columbia.edu.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032.|Department of Pediatrics, Columbia University Medical Center, New York, NY 10032.
authors.forename: Adolfo A
authors.initials: AA
authors.lastname: Ferrando
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, NY 10032; rr2579@cumc.columbia.edu af2196@columbia.edu tp2151@columbia.edu.|Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032.
authors.forename: Teresa
authors.initials: T
authors.lastname: Palomero
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D045744:Cell Line, Tumor; D006147:Guanine / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics*; D006801:Humans; D019169:Jurkat Cells; D016411:Lymphoma, T-Cell, Peripheral / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D006147:Guanine
keywords: VAV1; gene fusion; mutation; peripheral T-cell lymphoma