Beyond ON and OFF: how divergent RHOA mutations converge in T-cell lymphoma
Javier Robles Valero
Centro de Investigación del Cáncer (CSIC, Universidad de Salamanca, FICUS)
RHOA mutations are recurrently found in peripheral T-cell lymphomas (PTCL), yet they represent an unusual oncogenic paradigm: tumors select both dominant-negative and gain-of-function variants with apparently opposite effects on canonical RHOA signaling. In this seminar, I will discuss how these divergent mutations nevertheless converge through a shared neomorphic signaling mechanism. Rather than acting through conventional RHOA outputs, PTCL-associated mutants acquire the ability to engage the proximal T-cell receptor machinery and promote NFAT activation. Mechanistic studies reveal an unexpected connection between RHOA maturation, prenylation and T-cell signaling. Using primary CD4+ T cells, adoptive-transfer lymphoma models and human AITL PDXs, we further show that this pathway contributes to lymphomagenesis and creates a pharmacologically actionable vulnerability. Together, these findings provide a unifying explanation for the apparently contradictory RHOA mutational landscape of T-cell lymphoma and illustrate how oncogenic mutations can acquire functions that are not predicted by their canonical biochemical classification