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Cytogenetic and molecular studies of Down syndrome individuals with leukemia
J J Shen1, B J Williams, A Zipursky
1Department of Human Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Insights
Children with Down syndrome (DS) have a significantly higher risk of leukemia. Transient leukemia (TL) and acute megakaryoblastic leukemia (ANLL-M7) in DS infants are linked to atypical genetic profiles and male sex.
Area of Science:
- Genetics
- Oncology
- Pediatrics
Background:
- Down syndrome (DS) is associated with a 14-30 fold increased risk of leukemia in children.
- Transient leukemia (TL) occurs almost exclusively in infants with DS.
- The underlying genetic mechanisms linking DS and leukemia are not fully understood.
Purpose of the Study:
- To investigate the cytogenetic and molecular basis of nondisjunction in Down syndrome individuals with leukemia.
- To identify genetic differences between DS patients with TL, ANLL-M7, and other leukemias.
Main Methods:
- Collected blood and/or tissue samples from 55 individuals (17 TL, 7 ANLL-M7, 31 other leukemias).
- Performed cytogenetic analysis to identify constitutional karyotypes.
- Conducted genetic mapping studies to assess disomic homozygosity.
Main Results:
- DS infants with TL and ANLL-M7 showed a significant increase in atypical constitutional karyotypes (mosaic trisomies, rings, isochromosomes).
- These cases were predominantly male.
- Increased frequency of disomic homozygosity, particularly in proximal 21q, was observed in DS individuals with TL and ANLL-M7.
Conclusions:
- Atypical karyotypes and specific genetic profiles are associated with TL and ANLL-M7 in Down syndrome.
- These findings suggest distinct genetic pathways contributing to leukemia development in DS patients.
- Further research into nondisjunction mechanisms may elucidate leukemia origins in DS.
Abstract:
There is an increased risk of leukemia in Down syndrome (DS) patients, with estimates ranging from 14 to 30 times the incidence rate observed for chromosomally normal children. Furthermore, one type of leukemia, called "transient leukemia" (TL), occurs almost exclusively in DS infants. The basis of the association between DS and leukemia is unknown, but we and others have hypothesized that it may be influenced by the mechanism of origin of the extra chromosome. Therefore, we initiated a cytogenetic and molecular study of nondisjunction in leukemia DS individuals. To date, we have obtained blood and/or tissue samples from 55 individuals consisting of 17 cases with TL, 7 cases of acute nonlymphocytic leukemia subtype M7 (ANLL-M7, or acute megakaryoblastic leukemia, postulated to be related to TL), and 31 cases of other forms of leukemia. Analysis of these cases suggests differences between DS children with TL and those with other types of leukemia or DS individuals with no history of leukemia. Specifically, the TL and ANLL-M7 cases have a highly significant increase in the frequency of "atypical" constitutional karyotypes (i.e., mosaic trisomies, rings, and/or isochromosomes) and are almost always male. Additionally, genetic mapping studies suggest an increase in the frequency of disomic homozygosity, especially in proximal 21q, in DS individuals with TL and ANLL-M7.