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August 15, 2002
MEDIA CONTACT: Joanna Downer
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Leukemia Gene Found in Children with Down Syndrome  

Scientists from Baltimore and Chicago have found a gene defect that seems to lead to leukemia in children with Down syndrome. The discovery might offer a way to speed accurate diagnosis and provide new targets for treating the cancer, they report in the Aug. 12 online version of Nature Genetics.

Children with Down syndrome are 10 to 20 times more likely than others to develop cancers of the blood and blood-forming tissues, especially acute megakaryoblastic leukemia (AMKL), an otherwise rare disease.

"If further analyses show this gene to be altered only in leukemia, it very likely could lead to tests to help in the early diagnosis of leukemia in children with Down syndrome," says Michael McDevitt, M.D., Ph.D., assistant professor of hematology at the Johns Hopkins School of Medicine, whose laboratory did some of the genetic sequencing for the study. "We'll need to analyze many more samples to know for sure."

By studying bone marrow samples from 76 leukemia patients and 21 healthy subjects, the scientists discovered that changes in a gene called GATA-1 were found only in the six patients with Down syndrome, all of whom had AMKL. The other patients, including four with AMKL but not Down syndrome, did not have the defect, says McDevitt.

The normal GATA-1 protein helps control the expression of other genes, particularly in certain kinds of blood cells. In mice missing GATA-1, precursor blood cells don't progress to become normal platelets and instead just continue to multiply. In humans, problems with GATA-1 have been linked to certain types of blood disorders within families.

The scientists from Johns Hopkins, the University of Maryland and the University of Chicago discovered that in leukemia patients with Down syndrome, the instructions for making the GATA-1 protein are shifted, resulting in a protein that is too short. John Crispino, Ph.D., and his colleagues at the University of Chicago discovered that the short protein still works but can't carry out all its normal functions.

The scientists also showed that there were no mutations in another possible genetic contributor to leukemia in Down syndrome, called RUNX1. RUNX1 is on chromosome 21, which is found in triplicate in Down syndrome and is the definitive chromosomal marker for the disorder.

"RUNX1 is mutated in other kinds of leukemia, but doesn't seem to be altered in AMKL patients with Down syndrome," says McDevitt. "From our work, GATA-1 appears to be the gene defect involved in these patients, but it's still possible, and perhaps even likely, that too much of a normal RUNX1 protein might be contributing, too."

The researchers are still working on figuring out exactly how the defective protein causes or is involved in perpetuating leukemia, says McDevitt. The studies were funded by the Aplastic Anemia and MDS International Foundation, the Cancer Research Foundation, the Picower Foundation and the Burroughs Wellcome Foundation.

Authors on the study are Joshua Wechsler, Marianne Greene, John Anastasi, Michelle LeBeau and Crispino, the University of Chicago; Devitt, Johns Hopkins School of Medicine; and Judith Karp, Greenebaum Cancer Center, University of Maryland.

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