1. E(mu)-TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction.
- Author
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Gorgun G, Ramsay AG, Holderried TA, Zahrieh D, Le Dieu R, Liu F, Quackenbush J, Croce CM, and Gribben JG
- Subjects
- Animals, Disease Progression, Gene Expression Profiling, Humans, Immunological Synapses drug effects, Immunological Synapses immunology, Immunological Synapses pathology, Lenalidomide, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Mice, Mice, Transgenic, Proto-Oncogene Proteins genetics, Signal Transduction drug effects, Signal Transduction immunology, T-Lymphocytes drug effects, Thalidomide analogs & derivatives, Thalidomide pharmacology, Disease Models, Animal, Immunotherapy, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Leukemia, Lymphocytic, Chronic, B-Cell therapy, Proto-Oncogene Proteins metabolism, T-Lymphocytes immunology, T-Lymphocytes pathology
- Abstract
Preclinical animal models have largely ignored the immune-suppressive mechanisms that are important in human cancers. The identification and use of such models should allow better predictions of successful human responses to immunotherapy. As a model for changes induced in nonmalignant cells by cancer, we examined T-cell function in the chronic lymphocytic leukemia (CLL) Emu-TCL1 transgenic mouse model. With development of leukemia, Emu-TCL1 transgenic mice developed functional T-cell defects and alteration of gene and protein expression closely resembling changes seen in CLL human patients. Furthermore, infusion of CLL cells into young Emu-TCL1 mice induced defects comparable to those seen in mice with developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating actin remodeling, and T cells exhibited dysfunctional immunological synapse formation and T-cell signaling, which was reversed by the immunomodulatory drug lenalidomide. These results further demonstrate the utility of this animal model of CLL and define a versatile model to investigate both the molecular mechanisms of cancer-induced immune suppression and immunotherapeutic repair strategies.
- Published
- 2009
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