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Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells

Nature volume 431, pages 1002–1007 (2004)Cite this article

Abstract

Haematopoietic stem cells (HSCs) sustain blood production throughout life. HSCs are capable of extensive proliferative expansion, as a single HSC may reconstitute lethally irradiated hosts1. In steady-state, HSCs remain largely quiescent and self-renew at a constant low rate, forestalling their exhaustion during adult life2,3. Whereas nuclear regulatory factors promoting proliferative programmes of HSCs in vivo and ex vivo have been identified4,5,6, transcription factors restricting their cycling have remained elusive. Here we report that the zinc-finger repressor Gfi-1 (growth factor independent 1), a cooperating oncogene in lymphoid cells7,8, unexpectedly restricts proliferation of HSCs. After loss of Gfi-1, HSCs display elevated proliferation rates as assessed by 5-bromodeoxyuridine incorporation and cell-cycle analysis. Gfi-1-/- HSCs are functionally compromised in competitive repopulation and serial transplantation assays, and are rapidly out-competed in the bone marrow of mouse chimaeras generated with Gfi-1-/- embryonic stem cells. Thus, Gfi-1 is essential to restrict HSC proliferation and to preserve HSC functional integrity.

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Figure 1: Immunophenotypic analysis of HSCs in Gfi-1-/- mice.
Figure 2: Function of Gfi-1-/- HSCs is compromised in bone marrow transplantation assays.
Figure 3: Gfi-1-/- HSCs initiate, but do not sustain, bone marrow haematopoiesis in chimaeric mice.
Figure 4: Gfi-1 restricts proliferation of HSCs in a cell-context-specific manner.

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Acknowledgements

We appreciate the assistance of M. Handley, H. Levine, J. LaVechio, C. Browne and A. Williams. H.H. was supported by an NCI Career Development award. S.H.O. is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by a Center of Excellence in Molecular Hematology award from the NIH-NIDDK.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Children's Hospital,

    Hanno Hock, Melanie J. Hamblen, Heather M. Rooke, Jeffrey W. Schindler, Shireen Saleque, Yuko Fujiwara & Stuart H. Orkin

  2. Department of Medical Oncology,

    Hanno Hock

  3. Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School,

    Hanno Hock & Stuart H. Orkin

  4. Howard Hughes Medical Institute, Boston, Massachusetts, 02115, USA

    Melanie J. Hamblen, Heather M. Rooke, Yuko Fujiwara & Stuart H. Orkin

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  1. Hanno Hock
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  2. Melanie J. Hamblen
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Correspondence to Stuart H. Orkin.

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Supplementary information

Supplementary Figure 1

Results of transplantation of sorted Gfi-1-/- HSCs (JPG 180 kb)

Supplementary Figure 2

Analysis of Proliferation of HSCs following transplantation (JPG 316 kb)

Supplementary Figure 3

Transplantation of Gfi-1b-/- fetal liver derived HSCs (JPG 300 kb)

Supplementary Table 1

List of primers used for real-time PCR (DOC 22 kb)

Legends for supplementary figures (DOC 30 kb)

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Hock, H., Hamblen, M., Rooke, H. et al. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431, 1002–1007 (2004). https://doi.org/10.1038/nature02994

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