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Distinct patterns of gained chromosomes in high hyperdiploid acute lymphoblastic leukemia with t(1;19)(q23;p13), t(9;22)(q34;q22) or MLL rearrangements

Leukemia volume 27, pages 974–977 (2013)Cite this article

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High hyperdiploidy (HeH; 51–67 chromosomes) is seen in ∼25% of childhood and ∼7% of adult acute lymphoblastic leukemia (ALL).1, 2 Cases display a massive gain of chromosomes that results in a characteristic pattern of trisomies X, 4, 6, 10, 14, 17, and 18 and tetrasomy 21. In rare instances (2–3% of HeH cases), childhood ALL with a high hyperdiploid chromosome number also harbor t(1;19)(q23;p13)/TCF3–PBX1 fusion, t(9;22)(q34;q11)/BCR–ABL1 fusion or 11q23/MLL rearrangements (t-HeH).3 In adult ALL, similar frequencies of HeH and t(1;19) [t(1;19)/der(19)t(1;19)-HeH] and 11q23/MLL [MLL-HeH] are seen, whereas HeH together with t(9;22) [t(9;22)-HeH] is more common; t(9;22) is found in ∼30% of cases with 51–67 chromosomes.2 When classifying ALL by genetics, t-HeH cases are usually grouped according to the translocation. Such cases appear to have a worse prognosis than ‘classic’ HeH (c-HeH) in both children and adults, although this is based on relatively small patient series.2, 4 It has been reported that patients with t(9;22)-HeH have a better outcome than those with t(9;22) in a diploid context; however, they still display a shorter event-free survival than c-HeH patients.2, 5, 6, 7 In this study, we have utilized single nucleotide polymorphism (SNP) array analysis to investigate nine t(9;22)-HeH and two MLL-HeH ALL patients (Supplementary Table 1). SNP array data from four previously published cases were also included;8 original case numbers 5, 6, 10 [t(9;22)-HeH] and 11 [t(4;11)(q21;q23)-HeH]. DNA was extracted according to standard methods from bone marrow samples acquired at diagnosis, and SNP array analyses were performed using the Human Omni-1 Quad BeadChip platform (Illumina, San Diego, CA, USA) according to the manufacturer’s instructions. Data analyses were done using the GenomeStudio v2011.1 software with Illumina Genome Viewer 1.9.0 (Illumina). In addition, data from ALL cases reported in the literature with 51–67 chromosomes and concurrent (a) t(9;22)(q34;q11), (b) t(4;11)(q21;q23) or t(11;19)(q23;p13), or (c) t(1;19)(q23;p13)/der(19)t(1;19) were extracted from the Mitelman Database of Chromosome Aberrations and Gene Fusions in Cancer,3 and data from adult ALL cases with 51–65 chromosomes and one of the above-mentioned rearrangements were extracted from the karyotype database held by the Leukemia Research Cytogenetics Group (LRCG), Newcastle University, UK.2 Specific gains and modal numbers were ascertained from G-banded karyotypes, as published or reported by clinical laboratories. Cases with a range of modal numbers were classified as having the highest modal number in the range.

Few MLL-HeH cases could be evaluated; 3 with SNP array analysis and 11 in the cytogenetic review, of which 10 cases from the literature and 1 from the LRCG database. All cases had modal numbers of 51–53 (Figure 1b; Supplementary Table 1), which differs from the pattern seen in c-HeH.9 This indicates that the underlying mechanism of the gains in MLL-HeH differs from c-HeH. Furthermore, the pattern of chromosomal gains appeared to be less specific than in c-HeH cases (Figure 2b); only chromosomes X, 4, 6, 13 and 21 were gained in >50% of the cases by either SNP array or G-banding analyses. Three (27%) of the cases with cytogenetic data had a stemline with the MLL rearrangement only, indicating that the HeH was a secondary chromosomal event. Taken together, the limited data suggest that the chromosomal gains seen in MLL-HeH cases are different from the high hyperdiploid pattern seen in the c-HeH group, both regarding the mechanism of formation and their pathogenetic outcome.

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Acknowledgements

This work was supported by grants from the Swedish Childhood Cancer Foundation, Swedish Cancer Fund and Swedish Research Council. AVM, CJH and LAC thank: (1) all members of the laboratory UKCCG for providing cytogenetic results, cell suspensions and cDNA; (2) the UK NCRI Children’s Cancer and Leukemia Group (CCLG) Leukemia Subgroup (formerly the UK Childhood Leukemia Working Party) and UK NCRI ALL Working Party, and their members, who designed and coordinated the clinical trials through which these patients were identified and on which they were treated; and (3) the Leukemia and Lymphoma Research for funding.

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  1. Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University, Lund, Sweden

    K Paulsson & B Johansson

  2. Leukaemia Research Cytogenetics Group, Northern Institute for Cancer Research, University of Newcastle, Newcastle Upon Tyne, UK

    C J Harrison, L Chilton & A V Moorman

  3. The Cytogenetic Laboratory, The University Hospital Rigshospitalet, Copenhagen, Denmark

    M K Andersen

  4. Department of Molecular Medicine and Surgery and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden

    A Nordgren

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Paulsson, K., Harrison, C., Andersen, M. et al. Distinct patterns of gained chromosomes in high hyperdiploid acute lymphoblastic leukemia with t(1;19)(q23;p13), t(9;22)(q34;q22) or MLL rearrangements. Leukemia 27, 974–977 (2013). https://doi.org/10.1038/leu.2012.263

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