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Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice

Ellyard, Julia I; Chia, Tiongsun; Rodriguez-Pinilla, Socorro-Maria; Martin, Jaime L; Hu, Xin; Navarro-Gonzalez, Manuel; Garcia, Juan F; Delfau-Larue, Marie-Helene; Montes-Moreno, Santiago; Gaulard, Philippe; Cook, Matthew C; Walters, Giles; Piris, Miguel A; Vinuesa, Carola

Description

Angioimmunoblastic T-cell lymphoma (AITL) is the second most common peripheral T-cell lymphoma with unusual clinical and pathologic features and a poor prognosis despite intensive chemotherapy. Recent studies have suggested AITL derives from follicular helper T (TFH) cells, but the causative molecular pathways remain largely unknown. Here we show that approximately 50% of mice heterozygous for the “san” allele of Roquin develop tumors accompanied by hypergammaglobulinemia by 6...[Show more]

dc.contributor.authorEllyard, Julia I
dc.contributor.authorChia, Tiongsun
dc.contributor.authorRodriguez-Pinilla, Socorro-Maria
dc.contributor.authorMartin, Jaime L
dc.contributor.authorHu, Xin
dc.contributor.authorNavarro-Gonzalez, Manuel
dc.contributor.authorGarcia, Juan F
dc.contributor.authorDelfau-Larue, Marie-Helene
dc.contributor.authorMontes-Moreno, Santiago
dc.contributor.authorGaulard, Philippe
dc.contributor.authorCook, Matthew C
dc.contributor.authorWalters, Giles
dc.contributor.authorPiris, Miguel A
dc.contributor.authorVinuesa, Carola
dc.date.accessioned2014-02-19T22:43:39Z
dc.date.available2014-02-19T22:43:39Z
dc.identifier.issn0006-4971
dc.identifier.urihttp://hdl.handle.net/1885/11396
dc.description.abstractAngioimmunoblastic T-cell lymphoma (AITL) is the second most common peripheral T-cell lymphoma with unusual clinical and pathologic features and a poor prognosis despite intensive chemotherapy. Recent studies have suggested AITL derives from follicular helper T (TFH) cells, but the causative molecular pathways remain largely unknown. Here we show that approximately 50% of mice heterozygous for the “san” allele of Roquin develop tumors accompanied by hypergammaglobulinemia by 6 months of age. Affected lymph nodes displayed the histologic features diagnostic of AITL, except for the presence of expanded FDC networks. Accumulation of TFH cells preceded tumor development, and clonal rearrangements in the TCR-B genes were present in most tumors. Furthermore, TFH cells exhibited increased clonality compared with non-TFH cells from the same lymph nodes, even in the absence of tumors. Genetic manipulations that prevent TFH development, such as deletion of ICOS, CD28, and SAP, partially or completely abrogated tumor development, confirming a TFH-derived origin. Roquinsan/+ mice emerge as a useful model to investigate the molecular pathogenesis of AITL and for preclinical testing of therapies aimed at targeting dysregulated TFH cells or their consequences.
dc.description.sponsorshipThis work was supported by a Viertel Senior Medical Research Fellowship and National Health and Medical Research Council program and project grants (C.G.V.) and a National Health and Medical Research Council Overseas Biomedical Fellowship (J.I.E.).
dc.format11 pages
dc.publisherAmerican Society of Hematology
dc.rightshttp://www.sherpa.ac.uk/romeo/issn/0006-4971/ author cannot archive pre-print (ie pre-refereeing); author can archive post-print (ie final draft post-refereeing); author cannot archive publisher's version/PDF; on author's personal website and departmental website
dc.sourceBlood 120.4 (2012):812-821
dc.subjectangioimmunoblastic
dc.subjectT-cell
dc.subjectlymphoma-like tumors
dc.subjectmice
dc.titleHeterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice
dc.typeJournal article
local.identifier.citationvolume120
dcterms.dateAccepted2012-06-02
dc.date.issued2012-07-26
local.identifier.absfor111206 - Haematological Tumours
local.identifier.absfor110704 - Cellular Immunology
local.identifier.absfor111203 - Cancer Genetics
local.identifier.ariespublicationf5625xPUB2183
local.publisher.urlhttp://www.hematology.org/
local.type.statusPublished Version
local.contributor.affiliationEllyard, Julia I, Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University
local.contributor.affiliationChia, Tiongsun, Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University
local.contributor.affiliationMartin, Jaime L, Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University
local.contributor.affiliationHu, Xin, Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University
local.contributor.affiliationVinuesa, Carola G, Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University
local.bibliographicCitation.issue4
local.bibliographicCitation.startpage812
local.bibliographicCitation.lastpage821
local.identifier.doi10.1182/blood-2011-07-365130
local.identifier.absseo920102 - Cancer and Related Disorders
local.identifier.absseo920101 - Blood Disorders
local.identifier.absseo920108 - Immune System and Allergy
dc.date.updated2015-12-10T11:49:50Z
local.identifier.scopusID2-s2.0-84864483653
local.identifier.thomsonID000307445400015
CollectionsANU Research Publications

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