Somatic RHOA mutation in angioimmunoblastic T cell lymphoma

被引：491

作者：

Sakata-Yanagimoto, Mamiko ^{[1
]}

Enami, Terukazu ^{[1
]}

Yoshida, Kenichi ^{[2
,3
]}

Shiraishi, Yuichi ^{[4
]}

Ishii, Ryohei ^{[5
]}

Miyake, Yasuyuki ^{[1
]}

Muto, Hideharu ^{[1
]}

Tsuyama, Naoko ^{[6
]}

Sato-Otsubo, Aiko ^{[2
,3
]}

Okuno, Yusuke ^{[2
]}

Sakata, Seiji ^{[7
]}

Kamada, Yuhei ^{[1
]}

Nakamoto-Matsubara, Rie ^{[1
]}

Nguyen Bich Tran ^{[1
]}

Izutsu, Koji ^{[8
,9
]}

Sato, Yusuke ^{[2
,3
]}

Ohta, Yasunori ^{[10
]}

Furuta, Junichi ^{[11
]}

Shimizu, Seiichi ^{[12
]}

Komeno, Takuya ^{[13
]}

Sato, Yuji ^{[14
]}

Ito, Takayoshi ^{[15
]}

Noguchi, Masayuki ^{[16
]}

Noguchi, Emiko ^{[17
]}

Sanada, Masashi ^{[2
,3
]}

Chiba, Kenichi ^{[4
]}

Tanaka, Hiroko ^{[18
]}

Suzukawa, Kazumi ^{[1
,19
]}

Nanmoku, Toru ^{[19
]}

Hasegawa, Yuichi ^{[1
]}

Nureki, Osamu ^{[5
]}

Miyano, Satoru ^{[4
,18
]}

Nakamura, Naoya ^{[20
]}

Takeuchi, Kengo ^{[6
,7
]}

Ogawa, Seishi ^{[2
,3
]}

Chiba, Shigeru ^{[1
,21
]}

机构：

[1] Univ Tsukuba, Fac Med, Dept Hematol, Tsukuba, Ibaraki, Japan

[2] Univ Tokyo, Grad Sch Med, Cancer Genom Project, Tokyo, Japan

[3] Kyoto Univ, Grad Sch Med, Dept Pathol & Tumor Biol, Kyoto, Japan

[4] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab DNA Informat Anal, Tokyo, Japan

[5] Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Tokyo 113, Japan

[6] Japanese Fdn Canc Res, Inst Canc, Div Pathol, Tokyo 170, Japan

[7] Japanese Fdn Canc Res, Inst Canc, Pathol Project Mol Targets, Tokyo 170, Japan

[8] Toranomon Gen Hosp, Dept Hematol, Tokyo, Japan

[9] Okinaka Mem Inst Med Res, Tokyo, Japan

[10] Toranomon Gen Hosp, Dept Pathol, Tokyo, Japan

[11] Univ Tsukuba, Dept Dermatol, Fac Med, Tsukuba, Ibaraki, Japan

[12] Tsuchiura Kyodo Gen Hosp, Dept Hematol, Tsuchiura, Ibaraki, Japan

[13] Natl Hosp Org, Mito Med Ctr, Dept Hematol, Mito, Ibaraki, Japan

[14] Tsukuba Mem Hosp, Dept Hematol, Tsukuba, Ibaraki, Japan

[15] JA Toride Med Ctr, Dept Hematol, Toride, Japan

[16] Univ Tsukuba, Dept Pathol, Fac Med, Tsukuba, Ibaraki, Japan

[17] Univ Tsukuba, Dept Med Genet, Fac Med, Tsukuba, Ibaraki, Japan

[18] Univ Tokyo, Inst Med Sci, Ctr Human Genome, Lab Sequence Anal, Tokyo, Japan

[19] Univ Tsukuba Hosp, Dept Clin Lab, Tsukuba, Ibaraki, Japan

[20] Tokai Univ, Sch Med, Dept Pathol, Isehara, Kanagawa 25911, Japan

[21] Univ Tsukuba, Tsukuba Adv Res Alliance, Life Sci Ctr, Tsukuba, Ibaraki, Japan

来源：

NATURE GENETICS | 2014年 / 46卷 / 02期

关键词：

CRYSTAL-STRUCTURE; TET2; FREQUENT; PHOSPHORYLATION; ALIGNMENT; GTPASES; FAMILY; GENES; FORM;

D O I：

10.1038/ng.2872

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Angioimmunoblastic T cell lymphoma (AITL) is a distinct subtype of peripheral T cell lymphoma characterized by generalized lymphadenopathy and frequent autoimmune-like manifestations(1,2). Although frequent mutations in TET2, IDH2 and DNMT3A, which are common to various hematologic malignancies3,4, have been identified in AITL(5-8), 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.

引用

页码：171 / +

页数：8

共 34 条

[1]

[Anonymous], 2008, WHO CLASSIFICATION T

[2] XPLN, a guanine nucleotide exchange factor for RhoA and RhoB, but not RhoC [J].

Arthur, WT ;

Ellerbroek, SM ;

Der, CJ ;

Burridge, K ;

Wennerberg, K .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (45) :42964-42972

[3] GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo [J].

Bustelo, Xose R. ;

Sauzeau, Vincent ;

Berenjeno, Inmaculada M. .

BIOESSAYS, 2007, 29 (04) :356-370

[4] IDH2 mutations are frequent in angioimmunoblastic T-cell lymphoma [J].

Cairns, Rob A. ;

Iqbal, Javeed ;

Lemonnier, Francois ;

Kucuk, Can ;

de Leval, Laurence ;

Jais, Jean-Philippe ;

Parrens, Marie ;

Martin, Antoine ;

Xerri, Luc ;

Brousset, Pierre ;

Chan, Li Chong ;

Chan, Wing-Chung ;

Gaulard, Philippe ;

Mak, Tak W. .

BLOOD, 2012, 119 (08) :1901-1903

[5] Initial genome sequencing and analysis of multiple myeloma [J].

Chapman, Michael A. ;

Lawrence, Michael S. ;

Keats, Jonathan J. ;

Cibulskis, Kristian ;

Sougnez, Carrie ;

Schinzel, Anna C. ;

Harview, Christina L. ;

Brunet, Jean-Philippe ;

Ahmann, Gregory J. ;

Adli, Mazhar ;

Anderson, Kenneth C. ;

Ardlie, Kristin G. ;

Auclair, Daniel ;

Baker, Angela ;

Bergsagel, P. Leif ;

Bernstein, Bradley E. ;

Drier, Yotam ;

Fonseca, Rafael ;

Gabriel, Stacey B. ;

Hofmeister, Craig C. ;

Jagannath, Sundar ;

Jakubowiak, Andrzej J. ;

Krishnan, Amrita ;

Levy, Joan ;

Liefeld, Ted ;

Lonial, Sagar ;

Mahan, Scott ;

Mfuko, Bunmi ;

Monti, Stefano ;

Perkins, Louise M. ;

Onofrio, Robb ;

Pugh, Trevor J. ;

Rajkumar, S. Vincent ;

Ramos, Alex H. ;

Siegel, David S. ;

Sivachenko, Andrey ;

Stewart, A. Keith ;

Trudel, Suzanne ;

Vij, Ravi ;

Voet, Douglas ;

Winckler, Wendy ;

Zimmerman, Todd ;

Carpten, John ;

Trent, Jeff ;

Hahn, William C. ;

Garraway, Levi A. ;

Meyerson, Matthew ;

Lander, Eric S. ;

Getz, Gad ;

Golub, Todd R. .

NATURE, 2011, 471 (7339) :467-472

[6]

Cheng Zhijie, 2010, Curr Chem Genomics, V4, P84, DOI 10.2174/1875397301004010084

[7] Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma [J].

Cleverley, SC ;

Costello, PS ;

Henning, SW ;

Cantrell, DA .

ONCOGENE, 2000, 19 (01) :13-20

[8] TET2 and DNMT3A Mutations in Human T-Cell Lymphoma [J].

Couronne, Lucile ;

Bastard, Christian ;

Bernard, Olivier A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2012, 366 (01) :95-96

[9] The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells [J].

de Leval, Laurence ;

Rickman, David S. ;

Thielen, Caroline ;

de Reynies, Aurelien ;

Huang, Yen-Lin ;

Delsol, Georges ;

Lamant, Laurence ;

Leroy, Karen ;

Briere, Josette ;

Molina, Thierry ;

Berger, Francoise ;

Gisselbrecht, Christian ;

Xerri, Luc ;

Gaulard, Philippe .

BLOOD, 2007, 109 (11) :4952-4963

[10] Mutation in TET2 in Myeloid Cancers [J].

Delhommeau, Francois ;

Dupont, Sabrina ;

Della Valle, Veronique ;

James, Chloe ;

Trannoy, Severine ;

Masse, Aline ;

Kosmider, Olivier ;

Le Couedic, Jean-Pierre ;

Robert, Fabienne ;

Alberdi, Antonio ;

Lecluse, Yann ;

Plo, Isabelle ;

Dreyfus, Francois J. ;

Marzac, Christophe ;

Casadevall, Nicole ;

Lacombe, Catherine ;

Romana, Serge P. ;

Dessen, Philippe ;

Soulier, Jean ;

Viguie, Franck ;

Fontenay, Michaela ;

Vainchenker, William ;

Bernard, Olivier A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2009, 360 (22) :2289-2301

← 1 2 3 4 →