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Functional differences between myeloid leukemia-initiating and transient leukemia cells in Down's syndrome

Leukemia volume 24, pages 1012–1017 (2010)Cite this article

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A Corrigendum to this article was published on 11 August 2010

Abstract

Children with constitutional trisomy 21 or Down's syndrome (DS) are predisposed to develop myeloid leukemia (ML) at a young age. DS-ML is frequently preceded by transient leukemia (TL), a spontaneously resolving accumulation of blasts during the newborn period. Somatic mutations of GATA1 in the blasts of TL and DS-ML likely function as an initiating event. We hypothesized that the phenotypic difference between TL and DS-ML is due to a divergent functional repertoire of the leukemia-initiating cells. Using an NOD/SCID model, we found that cells initiating DS-ML engrafted, disseminated to distant bone marrow sites, and propagated the leukemic clone in secondary recipients. In contrast, TL cells lacked the ability to expand and to migrate, but were able to persist in the recipient bone marrow. We found some evidence of genomic progression with 1 of 9 DS-ML samples and none of 11 TL samples harboring a mutation of N-RAS. The findings of this pilot study provide evidence for the functional impact of second events underlying the transformation of TL into DS-ML and a needed experimental tool for the functional testing of these promoting events.

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Acknowledgements

We thank Dr Alvin Zipursky for the inspiring discussions, Dr Mohamed Abdelhaleem for assistance with imaging, and the families of children with leukemia for their participation. This work was supported by the National Cancer Institute of Canada (Canadian Cancer Research Society), The Ontario Institute for Cancer Research, and The Hospital for Sick Children Foundation.

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Authors and Affiliations

  1. Developmental and Stem Cell Biology, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada

    J Chen, Y Li, P Wang & J K Hitzler

  2. Division of Cell and Molecular Biology, University Health Network, Toronto, Ontario, Canada

    M Doedens & J Dick

  3. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    M Doedens & J Dick

  4. Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada

    M Shago

  5. Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada

    J K Hitzler

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  1. J Chen
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Correspondence to J K Hitzler.

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John E Dick declares research contracts with CSL and Arius.

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Chen, J., Li, Y., Doedens, M. et al. Functional differences between myeloid leukemia-initiating and transient leukemia cells in Down's syndrome. Leukemia 24, 1012–1017 (2010). https://doi.org/10.1038/leu.2010.30

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