by Weici Zhang, Masanobu Tsuda, Guo-Xiang Yang, Koichi Tsuneyama, Xiao-Song He, Aftab A. Ansari, William M. Ridgway, Ross L. Coppel, Zhe-Xiong Lian, Patrick S.C. Leung, M. Eric Gershwin
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 TGFßRII (dnTGFßRII) 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 dnTGFßRII mice between 10 weeks and 10 months of age associated with a predominant infiltration of CD4-CD8-TCRß+NK1.1+ or CD8+TCRß+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 dnTGFßRII homozygous compared to hemizygous mice. Further, 2×104 isolated lymphoma-like cells transplant disease by adoptive cell transfers. Collectively, our data demonstrate that increased copy number of dnTGFßRII is critical for development of lymphoma-like T cell infiltration.