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Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):764-769. doi: 10.1073/pnas.1608839114. Epub 2017 Jan 6.

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

Author information

1
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032.
2
Institute for Cancer Genetics, Columbia University, New York, NY 10032.
3
Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-University of Salamanca, 37007 Salamanca, Spain.
4
Department of Adult Hematology, Necker Hospital, 75015 Paris, France.
5
INSERM UMR163, Centre National de la Recherche Scientifique Équipe de Recherche Labellisée 8254, Institut Imagine, 75015 Paris, France.
6
Paris Descartes University, 75006 Paris, France.
7
Hemopathology Unit, European Institute of Oncology, 20139 Milan, Italy.
8
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065.
9
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032.
10
Instituto de Formación e Investigación, Hospital Universitario Marqués de Valdecilla, 39008 Santander, Spain.
11
Department of Pathology, Hospital Clinic, 08036 Barcelona, Spain.
12
Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, Miami, FL 33136.
13
Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL 33101.
14
INSERM U1170, 94805 Villejuif, France.
15
Université Paris-Sud, 91405 Orsay, France.
16
Gustave Roussy, 94805 Villejuif, France.
17
Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Spain.
18
Department of Systems Biology, Columbia University Medical Center, New York, NY 10032; rr2579@cumc.columbia.edu af2196@columbia.edu tp2151@columbia.edu.
19
Department of Biomedical Informatics, Columbia University Medical Center, New York, NY 10032.
20
Institute for Cancer Genetics, Columbia University, New York, NY 10032; rr2579@cumc.columbia.edu af2196@columbia.edu tp2151@columbia.edu.
21
Department of Pediatrics, Columbia University Medical Center, New York, NY 10032.

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.

KEYWORDS:

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

PMID:
28062691
PMCID:
PMC5278460
DOI:
10.1073/pnas.1608839114
[Indexed for MEDLINE]
Free PMC Article

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