Enforced expression of Lin28b leads to impaired T-cell development, release of inflammatory cytokines, and peripheral T-cell lymphoma

• Published in: Blood 2012-08, Vol.120 (5), p.1048-1059
• Main Authors: Beachy, Sarah H., Onozawa, Masahiro, Chung, Yang Jo, Slape, Chris, Bilke, Sven, Francis, Princy, Pineda, Marbin, Walker, Robert L., Meltzer, Paul, Aplan, Peter D.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - pathology; Cytokines - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Female; Hematologic and hematopoietic diseases; Inflammation Mediators - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoid Neoplasia; Lymphoma, T-Cell, Peripheral - genetics; Lymphoma, T-Cell, Peripheral - immunology; Lymphoma, T-Cell, Peripheral - metabolism; Lymphoma, T-Cell, Peripheral - pathology; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; RNA-Binding Proteins; T-Lymphocytes - metabolism; T-Lymphocytes - physiology; Transfection; Transgenes - genetics
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2012-01-401760

LIN28A and LIN28B, the mammalian homologs of lin-28, are implicated in malignant transformation in part because of their ability to promote degradation of the let-7 family of miRs. In the present study, we show that overexpression of Lin28b in vivo leads to an aggressive peripheral T-cell lymphoma (PTCL) characterized by widespread infiltration of parenchymal organs with malignant CD4+ cells. Similar to patients with PTCL, Lin28b-transgenic mice show signs of inflammation such as eosinophilia, increased C-reactive protein, release of inflammatory cytokines, and pleural effusion. The PTCLs that develop in Lin28b mice are derived from activated T cells and show decreased let-7 expression, increased Il6 expression, activation of NF-κB, and infiltration of B cells, all resulting in an inflammatory microenvironment. In addition, LIN28B is overexpressed 7.5-fold in PTCL patient samples compared with activated CD4+ cells. The results of the present study demonstrate for the first time that Lin28b can transform primary cells in vivo, identify a previously unsuspected link between Lin28b and PTCL, and provide a unique animal model for the study of PTCL biology and therapy.