Evidence for a single‐step mechanism in the origin of hyperdiploid childhood acute lymphoblastic leukemia

Abstract

High hyperdiploidy (>50 chromosomes) in childhood acute lymphoblastic leukemia (ALL) is characterized by nonrandom multiple trisomies and tetrasomies involving in particular chromosomes X, 4, 6, 8, 10, 14, 17, 18, and 21. This characteristic karyotypic pattern, the most common in pediatric ALL, may arise via a tetraploid state with subsequent loss of chromosomes, by sequential gains of chromosomes in consecutive cell divisions, or by simultaneous gain of chromosomes in a single mitosis. These alternatives may be distinguished by investigation of the allelic ratios of loci on the tetrasomic and disomic chromosomes. Previous studies of tetrasomy 21 and of the occurrence of uniparental disomies (UPDs) have suggested that the most likely mechanism is simultaneous gain. However, the other pathways have not been definitely excluded because complete analyses of all disomies and tetrasomies have never been performed. In the present study, we investigated 27 hyperdiploid ALLs by using 58 polymorphic microsatellite markers mapped to 23 of the 24 human chromosomes. Twenty-six tetrasomies were analyzed (involving chromosomes X, 8, 10, 14, 18, and 21), and the frequency of UPDs was determined in 10 cases. In total, 200 chromosomes were studied. Equal allele dosage was observed in 24 of 26 tetrasomies, and only 7 UPDs were found. These data strongly suggest that hyperdiploidy in childhood ALL generally arises by a simultaneous gain of all additional chromosomes in a single abnormal mitosis.

Genetic landscape of high hyperdiploid childhood acute lymphoblastic leukemia

“…Several studies have shown that wUPIDs are present in 25-30% of cases from this subgroup (23)(24)(25), in line with our finding of 27%. We have proposed previously that this overrepresentation may reflect the underlying mechanism by which the hyperdiploidy originates (2), in particular because the previous studies have not shown wUPID for specific chromosomes (23)(24)(25). However, our present data indicate that there also is a nonrandom pattern of wUPIDs in high hyperdiploid ALL (Fig.…”

“…[Samples from parents had been obtained as part of a previous investigation (23).] The analysis could be performed in three of the cases with wUPID9 (cases 3, 8, and 50) and in two of the cases with wUPID11 (cases 1 and 50).…”

Chromosome 14 copy number-dependent IGH gene rearrangement patterns in high hyperdiploid childhood B-cell precursor ALL: implications for leukemia biology and minimal residual disease analysis

“…17 They confirm, together with a high frequency of related IGH rearrangements and of three or more rearrangements in almost 45% of cases, the notion that the nondisjunction of chromosomes leading to an HeH karyotype affects a cell at the beginning of IGH recombination. 23,24 In line with this notion, the other half of HeH leukemias with no more than two IGH rearrangements supposedly have duplicated a chromosome 14 with a preexisting (V H )DJ H rearrangement that is not modified anymore thereafter. Additional features from SB also fit in this concept, as the vast majority of cases lack IGH germ-line configuration or deletions.…”

Mutations of FLT3, NRAS, KRAS, and PTPN11 are frequent and possibly mutually exclusive in high hyperdiploid childhood acute lymphoblastic leukemia

“…Among the 78 high hyperdiploid ALLs investigated, 26 (33%) harbored mutations of FLT3, The karyotypes of these cases have been previously published (Heim et al, 1990;Kö hler et al, 1996;Andreasson et al, 1998Andreasson et al, , 2000Paulsson et al, 2003Paulsson et al, , 2005Paulsson et al, , 2006Schaad et al, 2006 …”

“…However, considering that the hyperdiploid clone may already be present at birth but that there is a latency period of several years before overt leukemia (Panzer-Grü mayer et al, 2002;Maia et al, 2003Maia et al, , 2004, it seems unlikely that the tri-and tetrasomies alone are sufficient for leukemogenesis. Furthermore, it has been shown that a single abnormal mitosis underlies all chromosomal gains in most cases, indicating that the cell giving rise to the hyperdiploid clone harbored other genetic abnormalities, inducing the aberrant cell division and/or allowing it to survive such a drastic and sud-den aneuploidy (Onodera et al, 1992;Paulsson et al, 2003Paulsson et al, , 2005. G-banding, fluorescence in situ hybridization (FISH), conventional comparative genome hybridization (CGH), array-based CGH, and single nucleotide polymorphism array analyses only detect structural chromosomal changes in a subset of pediatric high hyperdiploid cases (Elghezal et al, 2001;Kristensen et al, 2003;Moorman et al, 2003;Paulsson et al, 2005Paulsson et al, , 2006Davidsson et al, 2006Davidsson et al, , 2007Mullighan et al, 2007;Strefford et al, 2007).…”