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Eµ-TCL1 Mice Represent a Model for Immunotherapeutic Reversal of Chronic Lymphocytic Leukemia-Induced T-Cell Dysfunction
Gullu Gorgun, Alan G. Ramsay, Tobias A. W. Holderried, David Zahrieh, Rifca Le Dieu, Fenglong Liu, John Quackenbush, Carlo M. Croce, John G. Gribben and Carlo M. Croce
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 15 (Apr. 14, 2009), pp. 6250-6255
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/40482076
Page Count: 6
You can always find the topics here!Topics: T lymphocytes, Chronic lymphocytic leukemia, B lymphocytes, Leukemia, Animal models, Mice, Transgenic animals, Gene expression, Actins, Synapses
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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) Eμ-TCL1 transgenic mouse model. With development of leukemia, Eμ-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 Eμ-TCL1 mice induced defects comparable to those seen in mice wjth developed leukemia, demonstrating a causal relationship between leukemia and the T-cell defects. Altered pathways involved genes regulating act in 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.
Proceedings of the National Academy of Sciences of the United States of America © 2009 National Academy of Sciences