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Acute Leukemias

Evolutionary trajectories of hyperdiploid ALL in monozygotic twins

Leukemia volume 29, pages 58–65 (2015)Cite this article

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Abstract

Identical twins have provided unique insights on timing or sequence of genetic events in acute lymphoblastic leukaemia (ALL). To date, this has mainly focused on ALL with MLL or ETV6-RUNX1 fusions, with hyperdiploid ALL remaining less well characterised. We examined three pairs of monozygotic twins, two concordant and one discordant for hyperdiploid ALL, for single-nucleotide polymorphism (SNP)-defined copy number alterations (CNAs), IGH/L plus TCR gene rearrangements and mutations in NRAS, KRAS, FLT3 and PTPN11 genes. We performed whole exome sequencing in one concordant twin pair. Potential ‘driver’ CNAs were low, 0–3 per case, and all were different within a pair. One patient had an NRAS mutation that was lacking from leukaemic cells of the twin sibling. By exome sequencing, there were 12 nonsynonymous mutations found in one twin and 5 in the other, one of which in SCL44A2 was shared or identical. Concordant pairs had some identical IGH/L and TCR rearrangements. In the twin pair with discordant hyperdiploid ALL, the healthy co-twin had persistent low level hyperdiploid CD19+ cells that lacked a CNA present in the ALL cells of her sibling. From these data, we propose that hyperdiploid ALL arises in a pre-B cell in utero and mutational changes necessary for clinical ALL accumulate subclonally and postnatally.

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Acknowledgements

This work was supported by Leukaemia & Lymphoma Research (to CMB, MG, AMF and SMC), The Kay Kendall Leukaemia Fund (to MG, AMF and SMC) and The Institute of Cancer Research (to LK and MG). DA is supported by the International Society for Advancement of Cytometry. DA and the Institute of Cancer Research acknowledge the support of the European Commission under the Marie Curie Intra-European Fellowship Programme. The contents of this paper reflect only the authors’ views and not the views of the European Commission. We thank Dr Iwanka Kozarewa, ICR tumour profiling unit, colleagues in exome sequencing, the children and their families for allowing the storage of biological material for research and The UK Cell Bank for releasing biological material for this project. We also thank professor Anthony Moorman, Northern Institute for Cancer Research, Newcastle, UK, for providing cytogenetic data on the samples provided by the Cell Bank and Dr Kajsa Paulsson, Department of Clinical Genetics, Lund University, Sweden, for providing a personal communication with regard to hyperdiploid ALL sequencing data. This project was part of the EHA-ASH Translational Research Training in Hematology (TRTH) Programme and NIHR Clinical Fellowship for CMB.

Author contributions

CMB: conducted genetic analysis (SNP arrays, FISH) on samples and drafted paper; DA: carried out all IGH/L and TCR clonal analyses and helped draft paper; AMF: carried out candidate gene mutational screen; DW: carried out GeneScan profiling; SMC: preparation, storage and retrieval of cells, and assisted with FISH scoring; MM: provided clinical samples from twin pair; LK: supervised FISH studies; MG: designed study and drafted the paper.

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Author notes

  1. C M Bateman and D Alpar: These two authors contributed equally to this work.

Authors and Affiliations

  1. Centre for Evolution and Cancer, The Institute of Cancer Research, Sutton, UK

    C M Bateman, D Alpar, A M Ford, S M Colman, L Kearney & M Greaves

  2. Division of Molecular Pathology, Molecular Diagnostics, The Institute of Cancer Research, Sutton, UK

    D Wren

  3. Department of Haematology, University Hospital Southampton, Southampton, UK

    M Morgan

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  1. C M Bateman
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Correspondence to M Greaves.

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Bateman, C., Alpar, D., Ford, A. et al. Evolutionary trajectories of hyperdiploid ALL in monozygotic twins. Leukemia 29, 58–65 (2015). https://doi.org/10.1038/leu.2014.177

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