Original Article

You have full text access to this OnlineOpen article

Hematopoietic Stem Cell Defects in Mice with Deficiency of Fancd2 or Usp1†‡§

  1. Kalindi Parmar1,
  2. Jungmin Kim1,
  3. Stephen M. Sykes2,
  4. Akiko Shimamura3,
  5. Patricia Stuckert1,
  6. Kaya Zhu1,
  7. Abigail Hamilton1,
  8. Mary Kathryn Deloach1,
  9. Jeffery L. Kutok4,
  10. Koichi Akashi5,
  11. D. Gary Gilliland2,
  12. Alan D'andrea1,¶,*

Article first published online: 4 MAY 2010

DOI: 10.1002/stem.437

Issue

STEM CELLS

STEM CELLS

Volume 28, Issue 7, pages 1186–1195, July 2010

Additional Information

How to Cite

Parmar, K., Kim, J., Sykes, S. M., Shimamura, A., Stuckert, P., Zhu, K., Hamilton, A., Deloach, M. K., Kutok, J. L., Akashi, K., Gilliland, D. G. and D'andrea, A. (2010), Hematopoietic Stem Cell Defects in Mice with Deficiency of Fancd2 or Usp1. STEM CELLS, 28: 1186–1195. doi: 10.1002/stem.437

Author Information

  1. 1

    Departments of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA

  2. 2

    Departments of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA

  3. 3

    Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA

  4. 4

    Departments of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

  5. 5

    Departments ofImmunology, Dana Farber Cancer Institute, Boston, Massachusetts, USA

  1. Telephone: 617-632-2112; Fax: 617-632-5757

*Department of Radiation Oncology, Dana-Farber Cancer Institute, Division of Genomic Stability and DNA Repair, Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA

  1. †

    Author contributions: K.P.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript; J.K., S.M.S., A.S., J.K.: conception and design, collection and assembly of data, data analysis and interpretation; P.S., K.Z., A.H., M.K.D.: collection and assembly of data, data analysis and interpretation; K.A., D.G.G.: conception and design, interpretation of data; A.D.: conception and design, data interpretation, financial support, manuscript writing, final approval of manuscript.

  2. ‡

    First published online in STEM CELLSEXPRESS May 4, 2010.

  3. §

    Disclosure of potential conflicts of interest is found at the end of this article.

Publication History

  1. Issue published online: 20 JUL 2010
  2. Article first published online: 4 MAY 2010
  3. Manuscript Accepted: 20 APR 2010
  4. Manuscript Received: 2 FEB 2010

Funded by

  • NIH. Grant Numbers: RO1DK43889, RO1HL52725, U19A1067751

SEARCH

SEARCH BY CITATION

ARTICLE TOOLS

View Full Article with Supporting Information (HTML) Get PDF (1739K)

Keywords:

  • Hematopoiesis and Stem Cells;
  • Fancd2 mice;
  • Usp1 mice

Abstract

Fanconi anemia (FA) is a human genetic disease characterized by a DNA repair defect and progressive bone marrow failure. Central events in the FA pathway are the monoubiquitination of the Fancd2 protein and the removal of ubiquitin by the deubiquitinating enzyme, Usp1. Here, we have investigated the role of Fancd2 and Usp1 in the maintenance and function of murine hematopoietic stem cells (HSCs). Bone marrow from Fancd2−/− mice and Usp1−/− mice exhibited marked hematopoietic defects. A decreased frequency of the HSC populations including Lin-Sca-1+Kit+ cells and cells enriched for dormant HSCs expressing signaling lymphocyte activation molecule (SLAM) markers, was observed in the bone marrow of Fancd2-deficient mice. In addition, bone marrow from Fancd2−/− mice contained significantly reduced frequencies of late-developing cobblestone area-forming cell activity in vitro compared to the bone marrow from wild-type mice. Furthermore, Fancd2-deficient and Usp1-deficient bone marrow had defective long-term in vivo repopulating ability. Collectively, our data reveal novel functions of Fancd2 and Usp1 in maintaining the bone marrow HSC compartment and suggest that FA pathway disruption may account for bone marrow failure in FA patients. STEM CELLS 2010;28:1186–1195

View Full Article with Supporting Information (HTML) Get PDF (1739K)