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

Author:

Parmar Kalindi1,Kim Jungmin1,Sykes Stephen M.2,Shimamura Akiko3,Stuckert Patricia1,Zhu Kaya1,Hamilton Abigail1,Deloach Mary Kathryn1,Kutok Jeffery L.4,Akashi Koichi5,Gilliland D. Gary2,D'andrea Alan1

Affiliation:

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

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

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

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

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

Abstract

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.

Funder

NIH

Publisher

Oxford University Press (OUP)

Subject

Cell Biology,Developmental Biology,Molecular Medicine

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