RHOA Mutations Are a Hallmark of Angioimmunoblastic T-cell Lymphoma

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive subtype of peripheral T-cell lymphoma (PTCL) that accounts for approximately 20% of all T-cell lymphomas. Although recurrent mutations in TET2, IDH2, and DNMT3A that are common in other hematologic malignancies have been identified in AITL, the molecular mechanisms that specifically promote AITL development are unknown. Sakata-Yanagimoto and colleagues performed whole-exome sequencing on 6 AITL samples and identified a recurrent RHOA^G17V mutation in 3 AITL samples. Targeted RHOA sequencing in an extended AITL cohort identified RHOA^G17V mutations in 49 of 72 (68%) AITLs. Similarly, Palomero and colleagues analyzed the exomes of 12 PTCL cases and identified recurrent RHOA^G17V mutations in 22 of 35 (67%) AITLs. No RHOA^G17V mutations were identified in other hematologic malignancies other than in a subset of PTCL not otherwise specified that shared AITL features, suggesting that somatic RHOA mutations are a specific feature of AITL. Of note, most RHOA-mutant AITLs also harbored TET2 mutations, but TET2 mutations had higher allelic frequencies than RHOA mutations and were also found in normal T cells, suggesting that they occurred prior to a driving RHOA mutation. GTP binding by the RHOA^G17V mutant protein was severely reduced despite increased guanine nucleotide exchange factor (GEF) protein binding compared with wild-type RHOA, indicating that the G17V mutant protein is inactive and may act in a dominant-negative manner by sequestering GEF proteins. Indeed, the G17V mutant protein also suppressed activation-associated binding of wild-type RHOA to the rhotekin effector protein and reduced RHOA-dependent actin stress fiber formation and gene activation. Mechanistically, expression of wild-type RHOA, but not RHOA^G17V, slowed T-cell proliferation, raising the possibility that the RHOA^G17V mutation may promote AITL by abrogating tumor-suppressive functions of RHOA in the T-cell lineage.

Sakata-Yanagimoto M, Enami T, Yoshida K, Shiraishi Y, Ishii R, Miyake Y, et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet 2014;46:171–5.

Palomero T, Couronné L, Khiabanian H, Kim MY, Ambesi-Impiombato A, Perez-Garcia A, et al. Recurrent mutations in epigenetic regulators, RHOA and FYN kinase in peripheral T cell lymphomas. Nat Genet 2014;46:166–70.

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