Cancer-associated mutations in VAV1 trigger variegated signaling outputs and T-cell lymphomagenesis

© 2021 The Authors.Mutations in VAV1, a gene that encodes a multifunctional protein important for lymphocytes, are found at different frequencies in peripheral T-cell lymphoma (PTCL), non-small cell lung cancer, and other tumors. However, their pathobiological significance remains unsettled. After cataloguing 51 cancer-associated VAV1 mutations, we show here that they can be classified in five subtypes according to functional impact on the three main VAV1 signaling branches, GEF-dependent activation of RAC1, GEF-independent adaptor-like, and tumor suppressor functions. These mutations target new and previously established regulatory layers of the protein, leading to quantitative and qualitative changes in VAV1 signaling output. We also demonstrate that the most frequent VAV1 mutant subtype drives PTCL formation in mice. This process requires the concurrent engagement of two downstream signaling branches that promote the chronic activation and transformation of follicular helper T cells. Collectively, these data reveal the genetic constraints associated with the lymphomagenic potential of VAV1 mutant subsets, similarities with other PTCL driver genes, and potential therapeutic vulnerabilities.The X.R.B.’s project leading to these results has received funding from “la Caixa” Banking Foundation (HR20-00164), the Castilla-León autonomous government (CSI252P18, CSI145P20, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (RTI2018-096481-B-100), and the Spanish Association against Cancer (GC16173472GARC). J.R.-V. received funding from the Carlos III Health Institute (PI20/01724). X.R.B.’s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León autonomous government (CLC-2017-01). J.R-V. is supported by a senior postdoctoral contract of the Spanish Association against Cancer. L.F.-N contract has been supported by the Salamanca local section of the Spanish Association against Cancer. S.R.-F. and L.F.L.-M. contracts have been mostly supported by funding from the MSI (BES-2013-063573) and the Spanish Ministry of Education, Culture and Sports (L.F.L.-M., FPU13/02923), respectively. Subsequently, they both were supported by the CLC-2017-01 grant. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund