Article abstract
Nature Genetics 40, 51 - 60 (2008)
Published online: 11 November 2007 | Corrected online: 23 January 2008 | doi:10.1038/ng.2007.7
There is an Erratum (February 2008) associated with this Article.
PU.1 is a major downstream target of AML1 (RUNX1) in adult mouse hematopoiesis
Gang Huang1,2,8, Pu Zhang1,8, Hideyo Hirai1,3, Shannon Elf1, Xiaomei Yan2, Zhao Chen4, Steffen Koschmieder1,7, Yutaka Okuno1, Tajhal Dayaram1, Joseph D Growney5, Ramesh A Shivdasani4, D Gary Gilliland5, Nancy A Speck6, Stephen D Nimer3 & Daniel G Tenen1
Abstract
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.
- Hematology/Oncology Division, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Harvard Medical School, Boston, Massachusetts 02115, USA.
- Division of Hematologic Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
- Department of Microbiology, Kyoto Prefectural University of Medicine, Kyoto, Japan 602-8566.
- Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
- Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
- Department of Biochemistry, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
- Current address: Universitaetsklinikum Muenster, Muenster, 48149 Germany.
- These authors contributed equally to this work.
Correspondence to: Daniel G Tenen1 e-mail: dtenen@bidmc.harvard.edu
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