High hyperdiploid childhood acute lymphoblastic leukemia

Abstract

High hyperdiploidy (51-67 chromosomes) is the most common cytogenetic abnormality pattern in childhood B-cell precursor acute lymphoblastic leukemia (ALL), occurring in 25-30% of such cases. High hyperdiploid ALL is characterized cytogenetically by a nonrandom gain of chromosomes X, 4, 6, 10, 14, 17, 18, and 21 and clinically by a favorable prognosis. Despite the high frequency of this karyotypic subgroup, many questions remain regarding the epidemiology, etiology, presence of other genetic changes, the time and cell of origin, and the formation and pathogenetic consequences of high hyperdiploidy. However, during the last few years, several studies have addressed some of these important issues, and these, as well as previous reports on high hyperdiploid childhood ALL, are reviewed herein.

Relapsed childhood high hyperdiploid acute lymphoblastic leukemia: presence of preleukemic ancestral clones and the secondary nature of microdeletions and RTK-RAS mutations

“…Relapsed high hyperdiploid acute lymphoblastic leukemia J Davidsson et al Table 2 Partial chromosomal imbalances in paired diagnostic and relapsed samples from childhood high hyperdiploid acute lymphoblastic leukemias as at relapse of high hyperdiploid ALLs, 1,12,21 but their prognostic impact remains to be clarified, at least in the context of high hyperdiploidy. 29,30 Recently, deletions of IKZF1 were shown to be a predictor of poor outcome in high-risk pediatric B-cell progenitor ALL.…”

“…In addition, microdeletions of CDKN2A, ETV6, IKZF1, PAX5, RB1 and TCF3, and mutations in the FLT3, KRAS, NRAS and PTPN11 genes, all involved in the RTK-RAS signaling pathway, are relatively frequent. 1 In recent larger series of children with high hyperdiploid ALL, the event-free survival and overall survival rates have been B80 and 90%, respectively. [2][3][4] Thus, despite the generally very good prognosis, a substantial proportion of the cases relapse and some patients succumb to the disease.…”

High hyperdiploid childhood acute lymphoblastic leukemia: Chromosomal gains as the main driver event

“…It is associated with low white blood cell counts, age of 3-5 years, and a favorable prognosis, with overall survival rates >90% on current treatment protocols. 1 The characteristic genetic feature of high hyperdiploidy is chromosomal gains, mainly trisomies but also frequently tetrasomies; in contrast, monosomies and gain of more than 2 copies of a chromosome are extremely rare. The gains may involve any chromosome, but more than 70% of cases harbor CX, C4, C6, C10, C14, C17, C18, or C21.…”

“…The gains may involve any chromosome, but more than 70% of cases harbor CX, C4, C6, C10, C14, C17, C18, or C21. 1 Considering that most of the other leukemia subtypes are associated with specific fusion genes or mutations, it has been proposed that this hyperdiploidy is an epiphenomenon without any leukemogenic effect that is secondary to a hitherto cryptic event. However, numerous investigations using fluorescence in situ hybridization, PCR, array comparative genome hybridization, and single nucleotide polymorphism array analysis have failed to identify such a hidden primary somatic aberration.…”

“…However, numerous investigations using fluorescence in situ hybridization, PCR, array comparative genome hybridization, and single nucleotide polymorphism array analysis have failed to identify such a hidden primary somatic aberration. 1 We recently published a large next-generation sequencing (NGS) study of high hyperdiploid childhood ALL in which tumor/normal pairs were subjected to whole genome sequencing (WGS; n D 16) or whole exome sequencing (n D 35). 2 The data from this investigation confirmed that there is no cryptic fusion gene in high hyperdiploid childhood ALL, with only 3/16 cases displaying rearrangements resulting in chimeric genes by WGS and no recurrent rearrangements leading to fusion genes.…”