Article

Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431:1002-07

Division of Hematology/Oncology, Children's Hospital, Boston, Massachusetts 02115, USA.
Nature (Impact Factor: 42.35). 11/2004; 431(7011):1002-7. DOI: 10.1038/nature02994
Source: PubMed

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 hosts. In steady-state, HSCs remain largely quiescent and self-renew at a constant low rate, forestalling their exhaustion during adult life. Whereas nuclear regulatory factors promoting proliferative programmes of HSCs in vivo and ex vivo have been identified, 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, 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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    • "The transcription factor Gfi1 is expressed in multiple tissues, including haematopoietic progenitors and stem cells, lymphoid and myeloid cells (Karsunky et al., 2002; Hock et al., 2004; Yücel et al., 2004; Rosenbauer and Tenen, 2007; Wilson et al., 2010a; Lancrin et al., 2012). We have previously identified an enhancer that is located around 35 kb upstream of Gfi1 (referred to as the Gfi1-35 enhancer) within an intron of the neighbouring gene Evi5 (Wilson et al., 2010a). "
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    • "To inquire into molecular mechanisms that may be involved in the poor proliferative and differentiation potentials of ALL-lymphoid progenitors, the transcription of some genes relevant to the quiescence status of hematopoietic primitive cells was evaluated. Of note, transcriptional repressor growth factor independence-1 (Gfi-1), formerly identified as a bifunctional regulator of hematopoietic differentiation [33] [34] [35], was highly displayed by ALL progenitor cells. Its nuclear distribution suggests a possible biological role in the pathogenesis of this disease. "
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    • "Several TFs have been implicated in HSC self-renewal. Specifically, deletions of Etv6 (Hock et al., 2004b), PU.1 (Burda et al., 2010), Gfi1 (Hock et al., 2004a), or Gata2 (Rodrigues et al., 2005) result in adult HSC defects, whereas loss of Sox17 causes defects in fetal-liver HSCs (Kim et al., 2007). Gain-of-function studies have identified factors such as HoxB4, HoxA9, PU.1, Erdr1, and cFos that expand HSC activity (Deneault et al., 2009). "
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