Functionally divergent RHOA mutations drive peripheral T cell lymphoma development by engaging a common neomorphic pathway
Year: 2026
Type: article
Abstract: RHOA, a RAS superfamily member, is frequently mutated in peripheral T-cell lymphoma (PTCL). These mutations are puzzling because variants have opposite effects on conventional RHOA signaling: some (e.g., RHOAG17V) inhibit normal RHOA function, whereas others (e.g., RHOAC16R) are constitutively active. Here we show that all PTCL-associated RHOA mutants acquire a non-canonical VAV1-like activity that activates the transcription factor NFAT. This activity is mediated by complexes between mutant RHOA and the RAP1GDS1607 isoform, is enhanced by T-cell receptor stimulation, and requires components of the T-cell receptor–VAV1 pathway, including PLCγ1 and calcineurin. Unlike canonical RAS superfamily signaling, this neomorphic activity does not require prenylation, the lipid modification anchoring RHOA to membranes. Genetic or pharmacological disruption of this pathway impairs RHOA-mutant PTCL in mouse models and patient-derived cells. These findings explain how mutations with opposing canonical effects converge on a shared oncogenic mechanism and reveal a potential therapeutic vulnerability in RHOA-mutant PTCL. RHOA mutation variants, exerting opposite effects on canonical RHOA signaling, are associated with peripheral T-cell lymphomas (PTCL). Here, the authors show that different RHOA mutants share a neomorphic activity that activates the transcription factor NFAT to drive PTCL.
Source: Nature Communications
Institutions: Universidad de Salamanca, Instituto de Salud Carlos III, Centro de Investigación del Cáncer, Centro de Investigación Biomédica en Red de Cáncer, Consejo Superior de Investigaciones Científicas, Centro Andaluz de Biología Molecular y Medicina Regenerativa, Universidad de Sevilla, Weill Cornell Medicine
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
OpenAlex ID: W7225788710
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