Hyperdiploidy: the longest known, most prevalent, and most enigmatic form of acute lymphoblastic leukemia in children

Abstract

Hyperdiploidy is the largest genetic entity B-cell precursor acute lymphoblastic leukemia in children. The diagnostic hallmark of its two variants that will be discussed in detail herein is a chromosome count between 52 and 67, respectively. The classical HD form consists of heterozygous di-, tri-, and tetrasomies, whereas the nonclassical one (usually viewed as "duplicated hyperhaploid") contains only disomies and tetrasomies. Despite their apparently different clinical behavior, we show that these two sub-forms can in principle be produced by the same chromosomal maldistribution mechanism. Moreover, their respective array, gene expression, and mutation patterns also indicate that they are biologically more similar than hitherto appreciated. Even though in-depth analyses of the genomic intricacies of classical HD leukemias are indispensable for the elucidation of the disease process, the ensuing results play at present surprisingly little role in treatment stratification, a fact that can be attributed to the overall good prognoses and low relapse rates of the concerned patients and, consequently, their excellent treatment outcome. Irrespective of this underutilization, however, the detailed genetic characterization of HD leukemias may, especially in planned treatment reduction trials, eventually become important for further treatment stratification, patient management, and the clinical elucidation of outcome data. It should therefore become an integral part of all upcoming treatment studies.

Fig. 1. Defining criteria of classical and nonclassical HD forms of childhood ALL.

A Based on their number of chromosomes, aneuploid forms of childhood ALL can be subdivided into seven distinct categories. The defining thresholds for HD cases range from 52 to 58 or 67 chromosomes. Classical HD and near-triploid karyotypes contain di-, tri, and tetrasomies, hyperhaploid and hypodiploid ones only mono- and disomies. Nonclassical HD karyotypes contain only di- and tetrasomies. 28% of the hyperhaploid and 32% of the nonclassical HD cases are monoclonal, whereas 40% of them share both clones. Likewise, 34% of the hypodiploid and 24% of the near-triploid cases are monoclonal, whereas 42% of them are bi-clonal [9]. The projection of representative karyotypes (highlighted chromosomes) of a classical (B) and a nonclassical (C) case onto the 92 chromosomes of a diploid mitotic cell illustrates that both patterns can be produced by the same yet-undefined nondisjunction mechanism and, in principle, even in a single step. The daughter cells that obtain the highlighted set of chromosomes, which always contain a tetrasomy 21, can survive, whereas the ones which only receive the dimmed set that lacks chromosomes 21 will perish as a result. The karyotype of the classical case (B) is 57,XX,+X,+X,+4,+6,CN-LOH(9),+10,+14,+14,+17,+18,+21,+21 and that of the nonclassical case (C) is 52,XX,+X,+X,CN-LOH(1–8,10–13,15–20,22),+14,+14,+21,+21.

Fig. 2. What the comparative analysis of germline and acquired chromosome copy number and/or sequence variants reveals about the origin, development, and biology of HD leukemias.

Left side, top: the minimal common denominator of HD leukemia is always a bi-parental derived tetrasomy 21, irrespective of whether it arises in a constitutional normal or trisomic individual. Left side, middle: the duplication of either the wild-type or variant allele of pharmacologically relevant heterozygous genes, such as the thiopurine S-methyltransferase (TPMT) on chromosome 6 and/or the γ-glutamyl hydrolase (GGH) on chromosome 8, will produce two distinct leukemia genotypes with opposite drug sensitivities [34]. Left side, bottom: the ARID5B rs7090445-C risk allele is preferentially duplicated in HD blast cells [40]. Right side, top: the recombination of the immunoglobulin heavy chain (IGH) gene on chromosome 14 follows discrete consecutive steps during B-cell maturation. A clone with a disomy 14 can thus harbor a maximum of two unique rearrangements, whereas a clone with trisomy 14 can have three unique or one unique and two related rearrangements. Systematic analyses of such rearrangement patterns have shown that trisomy 14 is usually already present before the initiation of IGH recombination and thus prove that the maldistribution of the chromosomes is indeed the essential transforming event [162, 163]. Right side, middle: the analysis of acquired trisomy-associated heterozygous mutations informs about the sequence of events and the latency period between the nondisjunction event and their emergence. Mutations acquired before trisomy formation may affect either 2/3 or 1/3 of the duplicated homologs, whereas those that are acquired after trisomy formation can merely be present in 1/3 of the non-duplicated homologs [16, 55]. Right side, bottom: X inactivation (Xi) is a dosage-compensation mechanism in females that silences either the maternal or paternal chromosome with an equal likelihood during early fetal development. As in other HD-related trisomies, either one of the two parental X chromosomes can therefore be duplicated [164]. Notwithstanding this fact, however, it is always the active X (Xa) that is nonrandomly gained [165]. This outcome concords with the high expression of X-encoded genes and suggests that specific X-linked factors help to jumpstart and maintain the disease process [–63].