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

Hae Yong Yoo, Min Kyung Sung, Seung Ho Lee, Sangok Kim, Haeseung Lee, Seongjin Park, Sang Cheol Kim, Byungwook Lee, Kyoohyoung Rho, Jong Eun Lee, Kwang Hwi Cho, Wankyu Kim, Hyunjung Ju, Jaesang Kim, Seok Jin Kim, Won Seog Kim, Sanghyuk Lee, Young Hyeh Ko

Research output: Contribution to journalArticlepeer-review

308 Scopus citations

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.

Original languageEnglish
Pages (from-to)371-375
Number of pages5
JournalNature Genetics
Volume46
Issue number4
DOIs
StatePublished - Apr 2014

Bibliographical note

Funding Information:
We appreciate helpful discussion and comments from P.J. Park (Harvard Medical School). This work was supported by grants from the Samsung Biomedical Research Institute (SP2-B2-04 to Y.H.K., W.S.K. and H.Y.Y. and GE1-B2-071 to H.Y.Y.), the Samsung Cancer Research Institute (cancer genomics project SCRI-12-02), the National Research Foundation of Korea (NRF-2012M3A9D1054744 and NRF-2012M3A9B9036673 to S.L. and NRF-2011-0019745), the GIST (Gwangju Institute of Science and Technology) Systems Biology Infrastructure Establishment Grant through ERCSB (S.L. and J.K.) and the Ewha Global Top5 Grant of Ewha Womans University.

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