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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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
Externally publishedYes

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T-Cell Prolymphocytic Leukemia
B-Cell Chronic Lymphocytic Leukemia
T-Lymphocytes
Transgenic Mice
Leukemia
Animal Models
Immunological Synapses
T-Cell Leukemia
Neoplasms
Immunotherapy
Actins
Gene Expression
Pharmaceutical Preparations
Genes
Proteins

ASJC Scopus subject areas

  • General

Cite this

Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction. / Gorgun, Gullu; Ramsay, Alan G.; Holderried, Tobias A W; Zahrieh, David; Dieu, Rifca Le; Liu, Fenglong; Quackenbush, John; Croce, Carlo M.; Gribben, John G.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 15, 14.04.2009, p. 6250-6255.

Research output: Contribution to journalArticle

Gorgun, Gullu ; Ramsay, Alan G. ; Holderried, Tobias A W ; Zahrieh, David ; Dieu, Rifca Le ; Liu, Fenglong ; Quackenbush, John ; Croce, Carlo M. ; Gribben, John G. / Eμ- TCL1 mice represent a model for immunotherapeutic reversal of chronic lymphocytic leukemia-induced T-cell dysfunction. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 15. pp. 6250-6255.
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