Formation of a hyperdiploid karyotype in childhood acute lymphoblastic leukemia.
Hyperdiploidy with greater than or equal to 50 chromosomes is a frequent and distinct karyotypic pattern in the malignant cells of children with acute lymphoblastic leukemia. To understand better the mechanism of formation of the hyperdiploid karyotype, we studied 15 patients using 20 DNA probes that detect restriction fragment length polymorphisms. We first examined disomic chromosomes for loss of heterozygosity. Two patients had widespread loss of heterozygosity on all informative disomic chromosomes, and represent cases of near-haploid leukemia in which the chromosomes doubled. One other patient had loss of heterozygosity limited to chromosome 3; in this patient all of seven other informative disomic chromosomes retained heterozygosity. Loss of heterozygosity was not detected in the remaining 12 patients on a total of 87 informative disomic chromosomes. We then examined tetrasomic chromosomes for parental dosage. Of the 13 patients in whom widespread loss of heterozygosity was not present, 11 patients had tetrasomy 21; 10 of 11 (91%) had an equal dose of maternal and paternal alleles on chromosome 21 and only 1 of 11 (9%) had an unequal dose of parental alleles in a 3:1 ratio. These results suggest that the hyperdiploid karyotype usually arises by simultaneous gain of chromosomes from a diploid karyotype during a single abnormal cell division, and occasionally by doubling of chromosomes from a near-haploid karyotype. The hyperdiploidy in cases without widespread loss of heterozygosity is not caused by stepwise or sequential gains from a diploid karyotype or by losses from a tetraploid karyotype; the former should result in a 3:1 parental dosage for 67% of tetrasomic chromosomes (9% observed) and the latter should result in loss of heterozygosity for 33% of disomic chromosomes (1% observed). Additional studies of the molecular basis for this leukemia subtype are warranted.
Department of Pediatrics, University of Chicago, IL 60637.
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N
Onodera
N R
NR
McCabe
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CM
Rubin
D000293:Adolescent; D000782:Aneuploidy; D002648:Child; D002675:Child, Preschool; D002891:Chromosomes, Human, Pair 21; D005260:Female; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007621:Karyotyping; D008297:Male; D012150:Polymorphism, Restriction Fragment Length; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*