Researchers at Jefferson Medical College and the Kimmel Cancer Center at Thomas Jefferson University in Philadelphia have developed the first animal model of the most common type of human leukemia. The new model should enable scientists to gain both a better understanding of the biochemical and molecular mechanisms underlying the disease, chronic lymphocytic leukemia (CLL), while at the same time provide a testing ground for potential new drugs.
"This is a very important discovery because now we have an animal model to use to develop and test new drugs," says Carlo Croce, M.D., professor and chair of microbiology and immunology at Jefferson Medical College of Thomas Jefferson University and director of the Kimmel Cancer Center, who led the work. "The model indicates what initiates the malignancy and provides us with interesting new targets involved in the earliest steps in the disease."
Several years ago, Dr. Croce and his co-workers isolated a gene, TCL-1, located on chromosome 14, and implicated it in several types of human leukemias and lymphomas, such as T-cell CLL and adult T-cell leukemia. These cancers are characterized by chromosomal rearrangements and in turn the uncontrolled proliferation of T-cells, key infection fighting white blood cells. According to Dr. Croce, TCL-1 is also expressed in two other types of cancer: B-cell CLL and B-cell lymphoma.
"We were puzzled by the fact that all B-cell CLL expressed TCL-1," Dr. Croce explains. "Cytogenetically B-cell CLL and B-cell lymphoma do not show the translocations or rearrangements of the TCL-1 gene observed in T-cell tumors." To better understand why, Dr. Croce and his co-workers created transgenic mice in which TCL-1 essentially is put into overdrive in B-cells.
Surprisingly, they found that when the gene is hyperactive, it produces too much of its protein product, resulting in uncontrolled expansion of leukemic cells and a disease identical to human B-cell CLL. "We did not predi
Contact: Steve Benowitz
Thomas Jefferson University