Somatic RHOA mutation in angioimmunoblastic T cell lymphoma

Abstract

Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma characterized by generalized lymphadenopathy and frequent autoimmune-like manifestations. Although frequent mutations in TET2, IDH2 and DNMT3A, which are common to various hematologic malignancies, have been identified in AITL, the molecular pathogenesis specific to this lymphoma subtype is unknown. Here we report somatic RHOA mutations encoding a p.Gly17Val alteration in 68% of AITL samples. Remarkably, all cases with the mutation encoding p.Gly17Val also had TET2 mutations. The RHOA mutation encoding p.Gly17Val was specifically identified in tumor cells, whereas TET2 mutations were found in both tumor cells and non-tumor hematopoietic cells. RHOA encodes a small GTPase that regulates diverse biological processes. We demonstrated that the Gly17Val RHOA mutant did not bind GTP and also inhibited wild-type RHOA function. Our findings suggest that impaired RHOA function in cooperation with preceding loss of TET2 function contributes to AITL-specific pathogenesis.

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

“…In AITL, PTCL-NOS and CTCL subtypes, DNMT3A mutations cluster in the methyltransferase domain. Interestingly, only about 20% of these mutations are at position R882 [75,77,94,95,97], the variant commonly found in myeloid diseases acting as a negatively regulating hypomorphic protein [105]. Dnm3a -deficient mice develop a PTCL-like disease at a frequency of 12% and heterozygous animals at a rate of 10%, associated with hypomethylation and decreased TP53 activity [106].…”

“…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.…”

“…However, loss-of-function mutations have also been detected [121]. Of note, in AITL and related lymphomas, RHOA mutations were accompanied by TET2 mutations, suggesting that TET2 and subsequent RHOA mutations may pave the way for T-cell transformation [95]. The RHOA G17V mouse model has reduced T-cell numbers, but these cells display increased activation upon stimulation and skew toward T FH cell differentiation.…”

Romidepsin induces durable responses in patients with relapsed or refractory angioimmunoblastic T‐cell lymphoma

“…These results provide additional support for the use of romidepsin in relapsed/refractory AITL. Further study of responding patients, particularly in light of discoveries of frequent DNMT3A , TET2 , IDH2 , and RhoA mutations in AITL,16, 17 may lead to biomarkers for sensitivity to HDACi.…”