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

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

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    38 Citations (Scopus)


    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 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-β genes were present in most tumors. Furthermore, TFHcells 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.

    Original languageEnglish
    Pages (from-to)812-821
    Number of pages10
    Issue number4
    Publication statusPublished - 26 Jul 2012


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