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, 2×104 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.
Highlights
Transforming growth factor beta (TGFb) is a multifunctional protein that acts as an important regulator of cell growth, proliferation, differentiation, morphogenesis and inflammation
We demonstrated that mice homozygous for dnTGFbRII spontaneously developed lymphoma-like T cell infiltration involving both the spleen and liver with a significantly elevated pro-oncogene expression of Notch 1 and compared with the hemizygous dnTGFbRII mice (c-Myc)
When individual animals generated by intercrossing were examined for the liver infiltrating mononuclear cells (MNCs), two distinct subsets of littermates with TGFbRII transgene were found to have dramatically different (6- to 12-fold) numbers of liver infiltrating MNC (Figure 1A)
Summary
Transforming growth factor beta (TGFb) is a multifunctional protein that acts as an important regulator of cell growth, proliferation, differentiation, morphogenesis and inflammation. Alterations of specific components involved along the TGFb signaling pathway results in loss of TGFb receptor function and disruption of the intracellular TGFb signaling cascade. Such loss of TGFbR function is implicated in the pathogenesis of aortic pathology, various cancers and fibrotic and inflammatory disease [1,2,4]. We demonstrated that mice homozygous for dnTGFbRII spontaneously developed lymphoma-like T cell infiltration involving both the spleen and liver with a significantly elevated pro-oncogene expression of Notch 1 and c-Myc. Further, we demonstrated that 26104 lymphoma-like cells were able to transplant disease by adoptive cell transfer
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