title: Lymphoma-like T cell infiltration in liver is associated with increased copy number of dominant negative form of TGFβ receptor II.
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.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California Davis, Davis, California, United States of America.
authors.forename: Weici
authors.initials: W
authors.lastname: Zhang
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsuda
authors.forename: Guo-Xiang
authors.initials: GX
authors.lastname: Yang
authors.forename: Koichi
authors.initials: K
authors.lastname: Tsuneyama
authors.forename: Xiao-Song
authors.initials: XS
authors.lastname: He
authors.forename: Aftab A
authors.initials: AA
authors.lastname: Ansari
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
authors.forename: Ross L
authors.initials: RL
authors.lastname: Coppel
authors.forename: Zhe-Xiong
authors.initials: ZX
authors.lastname: Lian
authors.forename: Patrick S C
authors.initials: PS
authors.lastname: Leung
authors.forename: M Eric
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000818:Animals; D018628:Gene Dosage; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D013160:Splenic Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C497762:Notch1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D051881:Receptor, Notch1; D018125:Receptors, Transforming Growth Factor beta