May 22, 2002 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 predict this," he says. "We thought the mice would develop B-cell tumors like B-cell lymphomas, not one specific disease such as B-cell CLL." Dr. Croce and his co-workers at Fox Chase Cancer Center in Philadelphia and the Istituto Dermatopatico dell'Immacolata in Rome report their findings May 14 in the Proceedings of the National Academy of Sciences.
"We really don't know much about the genetic mechanism involved in the pathogenesis of CLL," Dr. Croce says. "What this tells us is that either the TCL-1 gene or another gene (s) in the TCL-1 pathway are involved in the initiation and maintenance of B-cell CLL. Now we can target drugs at TCL-1 or molecules that interact with TCL-1. Eventually, we'll discover other targets in the future now that we know this pathway is important."
According to Dr. Croce, because the mouse disease is nearly identical to human CLL, the model will enable scientists to investigate all of the steps involved in the development of the disease. It will also tell researchers whether - and which - drugs work best early or late in the development of the disease.
B-cell CLL is a disease of apoptosis, or programmed cell death, gone awry, he explains. Leukemia cells are not dividing or dying; instead they continue to live a very long time. The study results should "provide important clues about the regulation of programmed cell death - why leukemic cells don't die," Dr. Croce notes, "and help us understand genetic mechanisms involved."
There are as many as 10,000 new cases of B-cell CLL in the United States each year. The disease often strikes the elderly, and while incurable, is slow growing, often lasting as long as 10 to 20 years.
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