A recurrent inactivating mutation in RHOA GTPase in angioimmunoblastic T cell lymphoma

Abstract

The molecular mechanisms underlying angioimmunoblastic T cell lymphoma (AITL), a common type of mature T cell lymphoma of poor prognosis, are largely unknown. Here we report a frequent somatic mutation in RHOA (encoding p.Gly17Val) using exome and transcriptome sequencing of samples from individuals with AITL. Further examination of the RHOA mutation encoding p.Gly17Val in 239 lymphoma samples showed that the mutation was specific to T cell lymphoma and was absent from B cell lymphoma. We demonstrate that the RHOA mutation encoding p.Gly17Val, which was found in 53.3% (24 of 45) of the AITL cases examined, is oncogenic in nature using multiple molecular assays. Molecular modeling and docking simulations provided a structural basis for the loss of GTPase activity in the RHOA Gly17Val mutant. Our experimental data and modeling results suggest that the RHOA mutation encoding p.Gly17Val is a driver mutation in AITL. On the basis of these data and through integrated pathway analysis, we build a comprehensive signaling network for AITL oncogenesis.

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

“…RHOA mutations are the only frequent GTPase mutations described in PTCL, occurring predominantly in up to 70% of AITL patients as well as 20% of PTCL-NOS and 15% of ATLL cases [93–95,121]. RHOA is a member of the Rho family of small GTPases that links cell-surface receptors to different intracellular signaling proteins.…”

“…In its active GTP-bound state, RHOA functions in controlling the actin cytoskeleton and stress fibers [122]. The most prominent mutation is RHOA G17V which acts as a dominant-negative molecule, underpinning its tumor-suppressive function in T-cells [93–95]. Other mutations found frequently in ATLL were mostly located within the GTP-binding pocket, with the gain-of-function variant C16R as the most recurrent.…”

Aspects moléculaires des lymphomes T périphériques (1)

“…Les mutations d'IDH2 ont pour effet d'inhiber indirectement les oxydases dépendantes du 2-oxoglutarate et du fer, telles que les protéines de la famille TET [29]. Une mutation récurrente du gène RHOA (G17V) est observée chez environ 70 % des patients [24,25,30]. Elle est fréquemment associée aux mutations de TET2 et de DNMT3A [24,25].…”

“…Elle est impliquée dans nombre de processus cellulaires via l'activation de voies de signalisation variées. Fonctionnellement, la mutation RHOA G17V semble exercer un effet dominant négatif sur l'activité de la protéine normale, aboutissant à une perte de fonction [24,25,30]. L'analyse transcriptomique montre que la mutation RHOA G17V est associée à l'activation de voies de signalisation telles que MAPK/ERK, PI3K/AKT, KRAS, RAC1, ou encore la voie alternative d'activation de NFB [30,31].…”

“…Fonctionnellement, la mutation RHOA G17V semble exercer un effet dominant négatif sur l'activité de la protéine normale, aboutissant à une perte de fonction [24,25,30]. L'analyse transcriptomique montre que la mutation RHOA G17V est associée à l'activation de voies de signalisation telles que MAPK/ERK, PI3K/AKT, KRAS, RAC1, ou encore la voie alternative d'activation de NFB [30,31]. D'un point de vue pronostique, les mutations de TET2 sont associées à une moins bonne survie sans progression [22], mais aucune des anomalies génétiques associées aux LAIT (TET2, DNMT3A, IDH2, RHOA G17V) n'a d'impact discernable sur la survie globale [22,23,25,31].…”