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Characterization of the TCL-1 transgenic mouse as a preclinical drug development tool for human chronic lymphocytic
Amy J Johnson1, David M Lucas, Natarajan Muthusamy
1Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA.
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.
Insights
A new TCL-1 transgenic mouse model mimics human chronic lymphocytic leukemia (CLL), showing therapeutic targets and drug sensitivity. This model aids in developing new CLL treatments by demonstrating in vivo drug activity and resistance.
Area of Science:
- Hematology
- Oncology
- Immunology
Background:
- Developing effective treatments for chronic lymphocytic leukemia (CLL) is challenging due to the absence of suitable animal models for pharmacological assessment.
- The TCL-1 transgenic mouse, which develops a chronic B-cell leukemia, presents a potential model for CLL research.
Purpose of the Study:
- To validate the TCL-1 transgenic mouse as a model for chronic lymphocytic leukemia (CLL).
- To assess the in vivo efficacy of fludarabine in this model and evaluate its potential for drug screening.
Main Methods:
- Confirmed the natural history of TCL-1 transgenic mouse leukemia.
- Characterized the expression of therapeutic targets (Bcl-2, Mcl-1, AKT, PDK1, DNMT1) and p53 status in murine lymphocytes.
- Administered low-dose fludarabine in vivo to assess clinical activity and survival.
Main Results:
- Transformed lymphocytes expressed key therapeutic targets and were sensitive to agents used in human CLL treatment.
- Fludarabine treatment in vivo led to reduced blood-lymphocyte counts, smaller spleen size, and prolonged survival (P = .046).
- Observed emergence of fludarabine resistance, mirroring human CLL progression.
Conclusions:
- The TCL-1 transgenic mouse model accurately reflects the clinical and therapeutic responses of human chronic lymphocytic leukemia (CLL).
- This model serves as a valuable in vivo tool for screening and developing novel therapeutic agents for CLL.
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