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Somatic RHOA mutation in angioimmunoblastic T cell lymphoma


Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma characterized by generalized lymphadenopathy and frequent autoimmune-like manifestations1,2. Although frequent mutations in TET2, IDH2 and DNMT3A, which are common to various hematologic malignancies3,4, have been identified in AITL5,6,7,8, 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.

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Figure 1: Discovery of a RHOA mutation encoding p.Gly17Val in PTCL by whole-exome sequencing.
Figure 2: Relationship between RHOA, TET2, IDH2 and DNMT3A mutations in PTCL.
Figure 3: Dominant-negative effect of the Gly17Val RHOA mutant on wild-type RHOA.
Figure 4: Effects of the Gly17Val RHOA mutant on transcriptional regulation and actin cytoskeleton formation in NIH3T3 cells.
Figure 5: Effect of Gly17Val RHOA on T cells.

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We thank Y. Okoshi, N. Obara, Y. Yokoyama, H. Nishikii, N. Kurita and M. Seki for contributing to sample collection and banking. We also thank Y. Sakashita and T. Takahashi for technical assistance, and S. Narumiya and I. Kitabayashi for efficient discussion. This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (22134006 to S.O.; 22130002, 24390241, 25112703 and 25670444 to S.C.; 25461407 to M.S.-Y.) and was supported by the Sagawa Foundation for Promotion of Cancer Research, the Naito Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research (M.S.-Y.).

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Authors and Affiliations



M.S.-Y. prepared DNA samples, sorted the tumor cells, resequenced the samples, and sorted and integrated information. T.E. analyzed the function of wild-type and mutant RHOA. K.Y. resequenced the samples and contributed to the resequencing data analyses. Y. Shiraishi, E.N., K.C., H.T. and S.M. performed bioinformatics analyses of the resequencing data. R.I. and O.N. created the model structure for mutant RHOA. Y.M., H.M., Y.K., R.N.-M., N.B.T., K.S., T.N., Y.H. and M.N. contributed to sample collection and preparation. N.T., S. Sakata, N.N. and K.T. immunostained specimens and performed pathohistological analyses. Y. Okuno and M.S. contributed to the resequencing. A.S.-O. and Yusuke Sato contributed to mRNA sequencing. K.I., Y. Ohta, J.F., S. Shimizu, T.K., Yuji Sato and T.I. collected samples. M.S.-Y., T.E., K.Y., S.O. and S.C. generated figures and tables, and wrote the manuscript. All authors participated in discussions and interpretation of the data and results.

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Correspondence to Seishi Ogawa or Shigeru Chiba.

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The authors declare no competing financial interests.

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Supplementary Figures 1–17, Supplementary Tables 1–14 and Supplementary Note (PDF 6808 kb)

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Sakata-Yanagimoto, M., Enami, T., Yoshida, K. et al. Somatic RHOA mutation in angioimmunoblastic T cell lymphoma. Nat Genet 46, 171–175 (2014).

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