Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1

Kalindi Parmar, Jungmin Kim, Stephen M. Sykes, Akiko Shimamura, Patricia Stuckert, Kaya Zhu, Abigail Hamilton, Mary Kathryn Deloach, Jeffery L. Kutok, Koichi Akashi, D. Gary Gilliland, Alan D'Andrea

Research output: Contribution to journalArticle

65 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1188-1195
Number of pages8
JournalStem Cells
Volume28
Issue number7
DOIs
Publication statusPublished - Jul 1 2010
Externally publishedYes

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Hematopoietic Stem Cells
Bone Marrow
Fanconi Anemia
Inborn Genetic Diseases
Medical Genetics
Lymphocyte Activation
Ubiquitin
DNA Repair
Maintenance
Population

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

Cite this

Parmar, K., Kim, J., Sykes, S. M., Shimamura, A., Stuckert, P., Zhu, K., ... D'Andrea, A. (2010). Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells, 28(7), 1188-1195. https://doi.org/10.1002/stem.437

Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. / Parmar, Kalindi; Kim, Jungmin; Sykes, Stephen M.; Shimamura, Akiko; Stuckert, Patricia; Zhu, Kaya; Hamilton, Abigail; Deloach, Mary Kathryn; Kutok, Jeffery L.; Akashi, Koichi; Gilliland, D. Gary; D'Andrea, Alan.

In: Stem Cells, Vol. 28, No. 7, 01.07.2010, p. 1188-1195.

Research output: Contribution to journalArticle

Parmar, K, Kim, J, Sykes, SM, Shimamura, A, Stuckert, P, Zhu, K, Hamilton, A, Deloach, MK, Kutok, JL, Akashi, K, Gilliland, DG & D'Andrea, A 2010, 'Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1', Stem Cells, vol. 28, no. 7, pp. 1188-1195. https://doi.org/10.1002/stem.437
Parmar K, Kim J, Sykes SM, Shimamura A, Stuckert P, Zhu K et al. Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. Stem Cells. 2010 Jul 1;28(7):1188-1195. https://doi.org/10.1002/stem.437
Parmar, Kalindi ; Kim, Jungmin ; Sykes, Stephen M. ; Shimamura, Akiko ; Stuckert, Patricia ; Zhu, Kaya ; Hamilton, Abigail ; Deloach, Mary Kathryn ; Kutok, Jeffery L. ; Akashi, Koichi ; Gilliland, D. Gary ; D'Andrea, Alan. / Hematopoietic stem cell defects in mice with deficiency of Fancd2 or Usp1. In: Stem Cells. 2010 ; Vol. 28, No. 7. pp. 1188-1195.
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