Activity Detail
Seminar
Out of the box roles of RHOA GTPase mutations in peripheral T cell lymphoma
Xosé R. Bustelo
The RAS-related GTPase RHOA is frequently mutated in peripheral T cell lymphoma (PTCL). Paradoxically, such mutants behave as either dominant negative (e.g., RHOAG17V) or constitutively active (e.g., RHOAC16R) versions according to the current regulatory paradigm for RAS superfamily members. To date, the mechanism by which these two apparent opposite functional subclasses of RHOA mutations drive T cell lymphomagenesis remains unclear. In my talk, I will present data demonstrating that, regardless of being dominant negative or constitutively active, all RHOA mutants found in PTCL unexpectedly show a common neomorphic function that leads to the stimulation of the transcription factor NFAT (nuclear factor of activated T cells). This de novo activity, which is mediated by the formation of heteromeric complexes between RHOA mutants and RAP1GDS1607, is further enhanced by the stimulation of the T cell receptor (TCR) and is dependent on critical signaling elements of the TCR and VAV1 pathways such as LAT, SLP76, PLCγ1, and calcineurin. I will also show that this neomorphic activity, in contrast to the current functional paradigm for RAS superfamily GTPases, does not require the prenylation of RHOA mutants. Furthermore, I will present results from genetic and pharmacological experiments demonstrating that this neomorphic pathway represents an actionable vulnerability for RHOA mutant-positive mouse and human PTCL. Collectively, all these findings provide a unified mechanism explaining how RHOA mutants with apparently opposing canonical functions drive PTCL, explain the higher prevalence of the RHOAG17V over other RHOA mutant versions in these cancers, and identify a potential therapeutic opportunity in the case of T cell lymphomas patients that are positive for RHOA mutations.