Resumen de tesis. Functional characterization of RHOA mutations in peripheral T-cell lymphomas

Abstract

[EN]RHOA is a small GTPase that belongs to the RHO proteins subfamily. During the last years, RHOA mutations have been identified in solid and hematological tumors. However, their pathobiological roles remain poorly characterized so far. In this thesis, we have functionally characterized these mutations, demonstrating that most of them lead to the inactivation of the GTPase activity of the protein. Focusing on the RHOA mutations described in peripheral T-cell lymphomas, we have proven that they activate the NFAT pathway independently of their canonical activity. This neomorphic activity is dependent on PLCɣ1, SLP76, and LAT. Proteomic analyses identified RAP1GDS1as a key effector for the neomorphic function of RHOA mutants. The RHOAG17V-driven tumors are sensitive to the pharmacological inhibition of NFAT activation. Altogether, our findings reveal novel pathobiological functions of RHOA and expand the current knowledge of the role of this protein in peripheral T-cell lymphomas. These data have unveiled an unexpected, neomorphic-like function of the RHOA mutants found in peripheral T-cell lymphomas. They also pinpoint new therapeutic opportunities for peripheral T-cell lymphoma patients. [ES]En este estudio se caracterizaron las mutaciones asociadas a RHOA en tumores. Se realizaron ensayos utilizando luciferasa para evaluar el efecto de las mutaciones en la actividad canónica de RHOA, encontrando que las mutaciones de RHOA pueden clasificarse en tres categorías funcionales: mutaciones similares a WT, mutaciones de ganancia de función (GOF) y mutaciones de pérdida de función (LOF). En cuanto a la localización en la estructura de la proteína, la mayoría de las mutaciones ubicadas en los dominios de cambio fueron principalmente LOF, mientras que las mutaciones ubicadas en los dominios de unión al GTP podrían exhibir efectos tanto GOF como LOF.