Fludarabine Boosts Survival - In the Mouse

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Blood First Edition Paper, prepublished online May 2, 2006

Submitted December 7, 2005

Accepted April 2, 2006

Characterization of the TCL-1 transgenic mouse as a pre- clinical

drug development tool for human chronic lymphocytic leukemia

Amy J , M Lucas, Natarajan Muthusamy, ,

, De Lay, Carlo M Croce, R Grever, and C

Byrd*

Division of Hematology and Oncology,Ohio State University

Division of Hematology and Oncology, Ohio State University

Department of Molecular Virology, Ohio State University

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 both relevant therapeutic targets (Bcl-2, Mcl-1,

AKT, PDK1, and DNMT1), wild type p53 mutational 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=0.046) as

compared to 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.