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February 13, 2003

SickKids researchers identify genetic events leading to leukemia in Down syndrome children

A research team at Sick Kids has identified important clues as to the genetic origins of acute megakaryoblastic leukemia in children with Down syndrome. The research team included Dr. Hans Hitzler, a staff physician in Haematology/Oncology and scientist-track investigator in Developmental Biology, Dr. Alvin Zipursky, former head of the Division of Haematology/Oncology, and Dr. Stephen Scherer, director of The Centre for Applied Genomics and a senior scientist in Genetics and Genomic Biology. This research was published online in the scientific journal Blood on February 13.

Children with Down syndrome have a 500-fold increased risk of developing acute megakaryoblastic leukemia (AMKL), a form of acute myeloid leukemia that is otherwise is rare in children. Newborns with Down syndrome may first develop “transient leukemia”, a form of megakaryoblastic leukemia that in most cases resolves without intervention after several months. However, in a significant number of these children full AMKL develops later in life. The current findings build on extensive clinical and experimental research by Dr. Zipursky, who pioneered treatment approaches for children with transient leukemia and first established a tissue bank of leukemic blast cells (the immature white blood cells) from children with Down syndrome.

Mutations in a key regulatory gene of human blood cell development, termed GATA1, had been recently found in the leukemic blast cells of Down syndrome children with full AMKL. The HSC research group demonstrated that these mutations are also present in blast cells of newborns with transient leukemia and, therefore, represent a very early event in the multi-step process that leads to AMKL in Down syndrome. By showing the same GATA1 mutation in a patient who had transient leukemia as a newborn and later developed full AMKL, the researchers were also able to demonstrate that full AMKL and transient leukemia likely arise from the same population of blood cells.

Next stages of research include determining the as yet unknown second event(s) – beyond GATA1 mutations – that lead to the development of full AMKL in children with Down syndrome who had transient leukemia as newborns. Further, the researchers are interested in understanding the events that allow the transient leukemia of Down syndrome to disappear in the majority of cases without intervention, as this knowledge may aid in the design of future treatments that specifically target the underlying disease mechanism in AMKL.

This research was supported by the Canadian Institutes of Health, Genome Canada, the Howard Hughes Medical Institute, and The Hospital for Sick Children Foundation.


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