Duplication and loss of chromosome 21 in two children with Down syndrome and acute leukemia

Abstract

Acute leukemia in Down syndrome (DS) is often associated with additional changes in the number or structure of chromosome 21. We present two DS patients whose leukemic karyotypes were associated with changes in chromosome 21 ploidy. Patient 1 developed acute lymphocytic leukemia (type L1); disomy for chromosome 21 was evident in all blast cells examined. Loss of the paternal chromosome in the leukemic clone produced maternal uniparental disomy with isodisomy over a 25-cM interval. The second patient had acute monoblastic leukemia (type M5) with tetrasomy 21 in all leukemic cells. DNA polymorphism analysis showed duplicate paternal chromosomes in the constitutional genotype. The maternal chromosome was subsequently duplicated in the leukemic clone. The distinct inheritance patterns of chromosome 21 in the blast cells of these patients would appear to indicate that leukemogenesis occurred by different genetic mechanisms in each individual.

Molecular allelokaryotyping of pediatric acute lymphoblastic leukemias by high-resolution single nucleotide polymorphism oligonucleotide genomic microarray

“…Even in 8 cases with Down syndrome who had trisomy 21 in their constitutional DNA, UPD of chromosome 21 was not detected. Although UPD of chromosome 21 in leukemic cells of patients with Down syndrome has been reported, 8 it may be a rare event in pediatric ALL.…”

“…A recent approach is single nucleotide polymorphism (SNP) analysis using an array-based technology 4,5 that allows identification of amplifications, deletions, and allelic imbalance, such as uniparental disomy (UPD [represents the doubling of the abnormal allele due to somatic recombination or duplication and loss of the other normal allele ]). [6][7][8] However, since this technique detects allelic dosage, it cannot detect balanced translocations.…”

Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies

“…Although isodisomy of a 25-cM interval was first described in children with Down syndrome who developed acute lymphoblastic leukemia by Rogan et al, 43 this genetic mechanism has received limited attention in hematologic malignancies until recently. The availability of automated allelotyping and the use of SNP and high-density arrays have been developed for high-resolution analysis of allelic losses and gains in tumors.…”

Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome

“…The most popular of these is increased gene dosage of a leukemia predisposition gene or hematopoiesis regulatory gene residing on chromosome 21. [14][15][16][17] This model is supported by the observation that acquisition of one or more additional chromosome 21 homologs is a common numerical abnormality in acute leukemia. [18][19][20] Even though there appears to be no direct correlation between the biologic features of AMKL and TMD and known function of genes identified on chromosome 21, it is likely that one or more of these genes are involved.…”