TY - JOUR
T1 - Heterozygosity for Roquinsan leads to angioimmunoblastic T-cell lymphoma-like tumors in mice
AU - Ellyard, Julia I.
AU - Chia, Tiongsun
AU - Rodriguez-Pinilla, Socorro Maria
AU - Martin, Jaime L.
AU - Hu, Xin
AU - Navarro-Gonzalez, Manuel
AU - Garcia, Juan F.
AU - Delfau-Larue, Marie Helene
AU - Montes-Moreno, Santiago
AU - Gaulard, Philippe
AU - Cook, Matthew C.
AU - Walters, Giles
AU - Piris, Miguel A.
AU - Vinuesa, Carola G.
PY - 2012/7/26
Y1 - 2012/7/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84864483653&partnerID=8YFLogxK
U2 - 10.1182/blood-2011-07-365130
DO - 10.1182/blood-2011-07-365130
M3 - Article
SN - 0006-4971
VL - 120
SP - 812
EP - 821
JO - Blood
JF - Blood
IS - 4
ER -