A unifying model for the oncogenic driver activity of functionally divergent RHOA mutations in Peripheral T Cell Lymphoma

Paradoxically, these RHOA mutations result in either dominant negative (e.g., RHOAG17V) or gain-of-function (e.g., RHOAC16R) over the canonical RHOA functions. The mechanism underlying the lymphomagenic activity of these two apparent opposite types of RHOA mutations is currently unclear.

Here, we demonstrate that, regardless of being dominant negative and gain-of-function, all RHOA mutants found in PTCL share the neomorphic activity of promoting the activation of nuclear factor of activated T cells (NFAT). This neomorphic activity requires the interaction of nonprenylated forms of these RHOA mutants with RAP1GDS1 and depends on the activation of the T cell receptor and its downstream signaling elements LAT, SLP76, and PLCG1.