1. Chromosomes and Gene Expression
  2. Stem Cells and Regenerative Medicine
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Functional evidence implicating chromosome 7q22 haploinsufficiency in myelodysplastic syndrome pathogenesis

  1. Jasmine C Wong
  2. Kelley M Weinfurtner
  3. Maria del pilar Alzamora
  4. Scott C Kogan
  5. Michael R Burgess
  6. Yan Zhang
  7. Joy Nakitandwe
  8. Jing Ma
  9. Jinjun Cheng
  10. Shann-Ching Chen
  11. Theodore T Ho
  12. Johanna Flach
  13. Damien Reynaud
  14. Emmanuelle Passegué
  15. James R Downing
  16. Kevin Shannon  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Celgene Corporation, United States
  3. Chinese Academy of Sciences, China
  4. St. Jude Children's Research Hospital, United States
  5. Thermo Fisher Scientific, United States
  6. Institute of Experimental Cancer Research, Germany
  7. Cincinnati Children's Hospital Medical Center, United States
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Cite this article as: eLife 2015;4:e07839 doi: 10.7554/eLife.07839

Abstract

Chromosome 7 deletions are highly prevalent in myelodysplastic syndrome (MDS), and likely contribute to aberrant growth through haploinsufficiency. We generated mice with a heterozygous germline deletion of a 2 Mb interval of chromosome band 5A3 syntenic to a commonly deleted segment of human 7q22, and show that mutant hematopoietic cells exhibit cardinal features of MDS. Specifically, the long-term hematopoietic stem cell (HSC) compartment is expanded in 5A3+/del mice, and the distribution of myeloid progenitors (MP) is altered. 5A3+/del HSCs are defective for lymphoid repopulating potential and show a myeloid lineage output bias. These cell autonomous abnormalities are exacerbated by physiologic aging and upon serial transplantation. The 5A3 deletion partially rescues defective repopulation in Gata2 mutant mice. 5A3+/del hematopoietic cells exhibit decreased expression of oxidative phosphorylation genes, increased levels of reactive oxygen species, and perturbed oxygen consumption. These studies provide the first functional data linking 7q22 deletions to MDS pathogenesis.

Article and author information

Author details

  1. Jasmine C Wong

    Department of Pediatrics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Kelley M Weinfurtner

    Department of Pediatrics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Maria del pilar Alzamora

    Department of Pediatrics, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Scott C Kogan

    Department of Laboratory Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Michael R Burgess

    Celgene Corporation, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Yan Zhang

    Unit of Hematopoietic Stem Cell and Transgenic Animal Models, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Joy Nakitandwe

    Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jing Ma

    Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jinjun Cheng

    Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shann-Ching Chen

    Thermo Fisher Scientific, South San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Theodore T Ho

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Johanna Flach

    Comprehensive Cancer Center, Institute of Experimental Cancer Research, Ulm, Germany
    Competing interests
    The authors declare that no competing interests exist.
  13. Damien Reynaud

    Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Emmanuelle Passegué

    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Department of Medicine, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. James R Downing

    Department of Pathology, St. Jude Children's Research Hospital, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Kevin Shannon

    Department of Pediatrics, University of California, San Francisco, San Francisco, United States
    For correspondence
    ShannonK@peds.ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: Study mice were housed in a specific pathogen-free facility at the University of California San Francisco, and all animal experiments were conducted in strict accordance with the protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the University of California, San Francisco (Approval number: AN091877-03).

Reviewing Editor

  1. Chi Van Dang, University of Pennsylvania, United States

Publication history

  1. Received: March 31, 2015
  2. Accepted: July 17, 2015
  3. Accepted Manuscript published: July 20, 2015 (version 1)
  4. Version of Record published: September 15, 2015 (version 2)

Copyright

© 2015, Wong et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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