January 21, 2003
SickKids researchers create novel mouse model for leukemia
TORONTO - Researchers at The Hospital for Sick Children (SickKids) and the University of Toronto (U of T) have created a mouse model relevant to the study of lymphoma and acute lymphoblastic leukemia (ALL). The mouse model will allow for further research into the genetic causes of leukemia and help define genetic markers that will improve prediction of the risk for spread of leukemia into the brain. This research is reported in the January 21 issue of the scientific journal Cancer Cell.
This work sheds light on how defects in the way cells detect and repair damaged chromosomes promote genetic instability and contribute to cancer. Broken chromosomes are dangerous to cells and all animals have systems to detect and repair them. Research has previously demonstrated that cancer cells are frequently defective in these DNA damage detection and repair systems.
In this study, researchers have shown that a pattern of genomic instability influences the behaviour of leukemia cells. The creation of the mouse model has enabled the group to study the molecular mechanisms by which leukemia cells invade and grow within the central nervous system. In addition, the researchers have created the first spontaneous mouse model of a serious complication of human leukemia, invasion of the brain by leukemia cells.
"Survival rates for children afflicted with acute lymphoblastic leukemia have improved dramatically. However, treatment failure for ALL and non-Hodgkin's lymphoma is frequently due to invasion of leukemia cells to the central nervous system. Several treatments prevent these invasions but cause significant mental impairment and increased risk of brain tumours. There is an urgent need to define how leukemia cells cross the blood-brain barrier, and to tailor therapy to the risk of leukemia in the central nervous system," said Dr. Rebecca Gladdy, first author of the study, a graduate student and a General Surgery resident in the Department of Surgery, U of T, and a National Cancer Institute of Canada research fellow.
"This mouse model provides an opportunity to identify genetic pathways that promote leukemia development and to define genetic markers that will improve prediction of risk for spread of leukemia into the brain," said Dr. Jayne Danska, the study's co-senior author, an SickKids senior scientist and an associate professor of Immunology at U of T. "The model will also aid us in identifying possible targets for therapeutic intervention."
Acute lymphoblastic leukemia is the most common cancer of childhood and represents about 80 per cent of all childhood leukemias. The disease occurs with an incidence of 30 cases per million per year and the incidence peaks between two and five years of age.
Dr. Cynthia Guidos, an SickKids senior scientist and an associate professor of Immunology at U of T is the other senior author of the study. Drs. Danska and Guidos collaborated with SickKids' Dr. James Rutka and Dr. Jeremy Squire of the University Health Network.
This research was supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society, Canadian Institutes of Health Research, Canadian Genetic Diseases Network of Centres of Excellence, and The Hospital for Sick Children Foundation.
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