Somatic RHOA mutation in angioimmunoblastic T cell lymphoma

Nat Genet. 2014 Feb;46(2):171-5. doi: 10.1038/ng.2872. Epub 2014 Jan 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Bromodeoxyuridine
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA-Binding Proteins / genetics*
  • Exome / genetics
  • Humans
  • Immunoblastic Lymphadenopathy / genetics*
  • Isocitrate Dehydrogenase / genetics
  • Jurkat Cells
  • Lymphoma, T-Cell, Peripheral / genetics*
  • Lymphoma, T-Cell, Peripheral / pathology
  • Mice
  • Molecular Sequence Data
  • Mutation, Missense / genetics
  • NIH 3T3 Cells
  • Proto-Oncogene Proteins / genetics*
  • Sequence Analysis, DNA
  • rhoA GTP-Binding Protein / genetics*

Substances

  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RHOA protein, human
  • Isocitrate Dehydrogenase
  • isocitrate dehydrogenase 2, human
  • IDH1 protein, human
  • TET2 protein, human
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • rhoA GTP-Binding Protein
  • Bromodeoxyuridine