1. Division of Hematology/Oncology, Children's Hospital,
2. Department of Medical Oncology and
3. Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School and the
4. Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA

Correspondence to: Stuart H. Orkin^1,3,4 Correspondence and requests for materials should be addressed to S.H.O. (Email: stuart_orkin@dfci.harvard.edu).

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 life^{2, 3}. Whereas nuclear regulatory factors promoting proliferative programmes of HSCs in vivo and ex vivo have been identified^{4, 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 cells^{7, 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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