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Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic leukemia
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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“In this model, the expression of the TCL1 oncogene is targeted to the B-cell lineage, resulting in the expansion of the B-1 cell compartment and the development of CD5+ B-cell leukemia resembling the aggressive form of human CLL(17, 18).”
From Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia (2010) · cites this paper as [18]
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Cited by
Dong, S., Harrington, B. K., Hu, E. Y., Greene, J. T., Lehman, A. M., Tran, M., Wasmuth, R. L., Long, M., Muthusamy, N., Brown, J. R., et al. (2018) · Journal of Clinical Investigation · doi:10.1172/jci99386 · Cited by 52
Self-citationInvolvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia
Sanchez-Aguilera, A., Rattmann, I., Drew, D. Z., Müller, L. U. W., Summey, V, Lucas, D. M., Byrd, J. C., Croce, C. M., Gu, Y., Cancelas, J. A., et al. (2010) · Leukemia · doi:10.1038/leu.2009.217 · Cited by 52
Self-citationValsecchi, R., Coltella, N., Magliulo, D., Bongiovanni, L., Scarfò, L., Ghia, P., Ponzoni, M., & Bernardi, R. (2020) · Open Biology · doi:10.1098/rsob.190262 · Cited by 12
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
- Publisher
- American Society of Hematology
- 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