Lymphoma-Like T Cell Infiltration in Liver Is Associated with Increased Copy Number of Dominant Negative Form of TGF beta Receptor II

• Authors: Weici Zhang, University of California Davis; Masanobu Tsuda, University of California Davis; Guo-Xiang Yang, University of California Davis; Koichi Tsuneyama, University of Toyama; Xiao-Song He, University of California Davis; Aftab Ansari, Emory University; William M. Ridgway, University of Cincinnati; Ross L. Coppel, Monash University; Zhe-Xiong Lian, University of Science & Technology of China; Patrick S.C. Leung, University of California Davis; M. Eric Gershwin, University of California Davis
• Journal Title: PLoS ONE
• Volume: Volume 7, Number 11
• Publisher: Public Library of Science | 2012-11-07, Pages e49413-e49413
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pone.0049413
• Subjects: Health Sciences, Pathology; Health Sciences, Immunology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; MULTIDISCIPLINARY SCIENCES; GROWTH-FACTOR-BETA; PRIMARY BILIARY-CIRRHOSIS; SPINAL MUSCULAR-ATROPHY; MOTOR-NEURON GENE; AUTOIMMUNE CHOLANGITIS; MICE; INTERLEUKIN-6; MECHANISMS; SURVIVAL; DIFFERENTIATION

Abstract

Hepatosplenic T cell lymphoma (HSTCL) is a distinct and lethal subtype of peripheral T cell lymphoma with an aggressive course and poor outcome despite multiagent chemotherapy. Contradictory literature, an unknown etiology, and poor response to treatment highlight the need to define the malignant process and identify molecular targets with potential for successful therapeutic interventions. Herein, we report that mice homozygously expressing a dominant negative TGFβRII (dnTGFβRII) under the control of the CD4 promoter spontaneously develop lymphoma-like T cell infiltration involving both spleen and liver. Splenomegaly, hepatomegaly and liver dysfunction were observed in homozygous dnTGFβRII mice between 10 weeks and 10 months of age associated with a predominant infiltration of CD4 - CD8 - TCRβ + NK1.1 + or CD8 + TCRβ + NK1.1 - T cell subsets. Notch 1 and c-Myc expression at the mRNA levels were significantly increased and positively correlated with the cell number of lymphoid infiltrates in the liver of dnTGFβRII homozygous compared to hemizygous mice. Further, 2×10 4 isolated lymphoma-like cells transplant disease by adoptive cell transfers. Collectively, our data demonstrate that increased copy number of dnTGFβRII is critical for development of lymphoma-like T cell infiltration.