FIGURE 3.

Representative karyotypes (A,C) and SNP/CGH array-derived whole genome views (B,D) of a postulated mononuclear-derived monoclonal (A,B) and a postulated binuclear-derived pure hyperdiploid ALL case (C,D). Affymetrix Cytoscan HD SNP arrays were processed according to the manufacturer’s recommendation and analyzed with the ChAS Software (Affymetrix, Santa Clara, CA, United States). The weighted log2 ratio, shown in the top (y-axis, left scale) indicates the respective copy numbers (y-axis, right scale) and the allele difference plot in the bottom shows the SNP distribution patterns (y-axis; homozygous AA = 1, heterozygous AB = 0, homozygous BB = −1). The x-axis indicates the chromosome numbers. Of note, corresponding mono-and biclonal hyperhaploid and hyperdiploid cell populations produce indistinguishable array patterns, so that cytogenetic, DNA-index and/or FISH analyses are required to keep them apart and to verify their presence. The unique example on the left stems from a female patient and concords with the schematic outline in Figure 2C. Apart from the obligatory heterozygous tetrasomy 21 (red frame), which is the mandatory trademark of such aneuploidies, it only contains homozygous disomies. Would it be not for this extraordinary array pattern, this case with 48 chromosomes would neither be recognized nor considered as belonging to the aneuploid entities referred to herein. As validated with chromosome and FISH analyses, the 1q duplication is only present in approximately 50% of the leukemic cells, which together with its homozygous nature confirms its secondary nature. The instructive hyperdiploid example from a male patient with 62 chromosomes and a somatic TP53 mutation on the right concords with the schematic outline in Figure 2A (kindly provided by Mayur Parihar, TATA Medical Center, Kolkata, India). Apart from exclusively homozygous disomies and heterozygous tetrasomies this case also contains homozygous trisomies of chromosomes 1, 6 and 7 (red frames). Provided one sticks to the one step mechanism of aneuploidization, the additional chromosomes cannot derive from the mitotic cell alone anymore. Moreover, since males have only one X, the presence of two isochromosomes Xp in addition to a normal one, can only mean that these two copies represent the co-segregated chromatids of an isochromosome Xp that already preexisted in the mitotic cell. The normal X can then only be the prematurely condensed one from the interphase cell. The isochromosome 17q, on the other hand, might have already preexisted before the fusion or evolved only thereafter. The Y chromosome was lost in this clone.