PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis

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  • An Erratum to this article was published on 01 February 2008


Both PU.1 (also called SFPI1), an Ets-family transcription factor, and AML1 (also called RUNX1), a DNA-binding subunit of the CBF transcription factor family, are crucial for the generation of all hematopoietic lineages, and both act as tumor suppressors in leukemia. An upstream regulatory element (URE) of PU.1 has both enhancer and repressor activity and tightly regulates PU.1 expression. Here we show that AML1 binds to functionally important sites within the PU.1 upstream regulatory element and regulates PU.1 expression at both embryonic and adult stages of development. Analysis of mice carrying conditional AML1 knockout alleles and knock-in mice carrying mutations in all three AML1 sites of the URE proximal region demonstrated that AML1 regulates PU.1 both positively and negatively in a lineage dependent manner. Dysregulation of PU.1 expression contributed to each of the phenotypes observed in these mice, and restoration of proper PU.1 expression rescued or partially rescued each phenotype. Thus, our data demonstrate that PU.1 is a major downstream target gene of AML1.

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Figure 1: AML1 regulates PU.1 through the −14 kb PU.1 URE.
Figure 2: AML1 regulates PU.1 both in embryonic and adult hematopoiesis.
Figure 3: Partial rescue of the AML1 knockout platelet and T-cell phenotypes by adjustment of the dosages of PU.1.
Figure 4: Altering the dosage of PU.1 enhances granulocytic and B-cell phenotypes in AML1 conditional knockout mice.
Figure 5: Restoration of PU.1 levels after retroviral transduction partially rescues the granulocytic and B-cell phenotypes in AML1 conditional knockout mice.
Figure 6: Genetic interaction of AML1 and PU.1 in B cells and myeloid cells.
Figure 7: Phenotypes of mice harboring targeted mutations of all three AML1 sites in the URE.

Change history

  • 23 January 2008

    In the version of this article initially published, the affiliation for Stephen D Nimer was incorrect. Dr. Nimer is affiliated with the Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center, New York, and not with Kyoto Prefectural University of Medicine. The error has been corrected in the PDF version of the article.


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We thank H. Singh for the MIGR1-PU.1 and MIGR1-PU.1-ER retroviral constructs, and M. Osato and members of the Tenen laboratory for critical discussions and suggestions. This work was supported by US National Institutes of Health grants CA41456 and CA66996 (to D.G.T.) and DK52208 (to S.D.N. and D.G.T.), Leukemia Lymphoma Society SCOR grants (to S.D.N. and D.G.T.) and Deutsche Forschungsgemeinschaft grant KO2155/1-1 (to S.K.).

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Correspondence to Daniel G Tenen.

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