Mouse Mimics Chronic Leukemia, Will Aid Drug Development

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A study by cancer researchers here reveals that a new strain of mice offers the first real animal model for an incurable form of chronic leukemia and should greatly aid the development of new drugs for the disease.

The mouse, called the TCL-1 transgenic mouse, develops a malignancy that closely mimics chronic lymphocytic leukemia (CLL). The lack of an animal model has greatly hampered the development of new treatments for CLL as well as research into its causes and the changes that drive drug resistance.

“This mouse strain shares many of the molecular and genetic features of human CLL, responds to drugs typically used to treat the disease and develops drug resistance that renders treatment ineffective, as often happens in CLL patients,” says principal investigator John C. Byrd, professor of internal medicine.

Byrd is a specialist in CLL at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James).

“The strain should be extremely valuable for the development and testing of both conventional drugs and those aimed at molecular targets for CLL.”

The findings are published in the Aug. 15 issue of the journal Blood, which includes a commentary about the significance of the research.

An estimated 10,000 Americans will develop CLL in 2006, and about 4,600 will die of the disease. The malignancy usually strikes people aged 50 or older and causes the proliferation of white blood cells called lymphocytes. Other effects include severe anemia and a high risk of viral, bacterial and fungal infections. Average survival after diagnosis is eight to 12 years. The standard treatment for CLL is the drug fludarabine, but the disease often becomes resistant to the drug.

This TCL-1 mouse strain was originally developed by OSU cancer researcher Carlo M. Croce, professor and chair, department of molecular virology, immunology and medical genetics and director of human cancer genetics at the OSUCCC-James.

Croce and his laboratory developed the mouse strain in 2002. The researchers engineered the animal so that key immune cells called B lymphocytes, or B cells, overproduce a protein called TCL-1. This overproduction causes the CLL-like disease, which develops about a year after birth, though how it does so is still unknown.

Human CLL is also a cancer of B cells, but it involves many chromosome and gene changes. Byrd and his laboratory are currently investigating whether human CLL cells also have high TCL-1 levels.

In this study, Byrd and his research team followed the development of the CLL-like disease in the mouse strain and found that the malignant mouse cells show many of the molecular characteristics of human CLL cells, such as expression of proteins called Bcl-2, Akt and normal p53.

The study also shows that the mouse disease mirrors CLL patients in its response to the drug fludarabine, including the development of resistance.

“This suggests that we can use this model to study the molecular changes that lead to fludarabine resistance and perhaps learn how to circumvent it,” says first author Amy J. Johnson, research scientist in Byrd’s laboratory.

Funding from the National Cancer Institute, the American Cancer Society (ACS), The Leukemia & Lymphoma Society and The D. Warren Brown Foundation supported this research. Byrd is also the D. Warren Brown Professor of Leukemia Research and a clinical scholar of The Leukemia & Lymphoma Society of America. Johnson was supported by an ACS Postdoctoral Fellowship.

Ohio State University

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