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Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia

Johnson, Amy J., Lucas, David M., Muthusamy, Natarajan, Smith, Lisa L., Edwards, Ryan B., De Lay, Michael D., Croce, Carlo M., Grever, Michael R., Byrd, John C.·2006·Blood

Abstract

Drug development in human chronic lymphocytic leukemia (CLL) has been limited by lack of a suitable animal model to adequately assess pharmacologic properties relevant to clinical application. A recently described TCL-1 transgenic mouse develops a chronic B-cell CD5+ leukemia that might be useful for such studies. Following confirmation of the natural history of this leukemia in the transgenic mice, we demonstrated that the transformed murine lymphocytes express relevant therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, and DNMT1), wild-type p53 status, and in vitro sensitivity to therapeutic agents relevant to the treatment of human CLL. We then demonstrated the in vivo clinical activity of low-dose fludarabine in transgenic TCL-1 mice with active leukemia. These studies demonstrated both early reduction in blood-lymphocyte count and spleen size and prolongation of survival (P = .046) compared with control mice. Similar to human CLL, an emergence of resistance was noted with fludarabine treatment in vivo. Overall, these studies suggest that the TCL-1 transgenic leukemia mouse model has similar clinical and therapeutic response properties to human CLL and may therefore serve as a useful in vivo tool to screen new drugs for subsequent development in CLL.

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Metadata

Authors
Johnson, A. J., Lucas, D. M., Muthusamy, N., Smith, L. L., Edwards, R. B., De Lay, M. D., Croce, C. M., Grever, M. R., & Byrd, J. C.
Affiliations
From the Division of Hematology and Oncology, Departments of Internal Medicine and Molecular Virology, Immunology, and Medical Genetics, College of Medicine, and Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus.
Venue
Blood
Published
2006-08-15
Volume
108
Issue
4
Pages
1334-1338
ISSN
  • 0006-4971
  • 1528-0020
Cited by
111
References
0
Language
en

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Johnson, A. J., Lucas, D. M., Muthusamy, N., Smith, L. L., Edwards, R. B., De Lay, M. D., Croce, C. M., Grever, M. R., & Byrd, J. C. (2006). Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia. Blood. https://doi.org/10.1182/blood-2005-12-011213