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

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87 Scopus citations

Abstract

Preclinical animal models have largely ignored the immune-sup-pressive 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 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.

Original languageEnglish (US)
Pages (from-to)6250-6255
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number15
DOIs
StatePublished - Apr 14 2009

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    Gorgun, G., Ramsay, A. G., Holderried, T. A. W., Zahrieh, D., Dieu, R. L., Liu, F., Quackenbush, J., Croce, C. M., & Gribben, J. G. (2009). Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 106(15), 6250-6255. https://doi.org/10.1073/pnas.0901166106