A distal single nucleotide polymorphism alters long-range reguiavon of the PU-1 gene in acute myeloid leukemia
2007 | journal article. A publication with affiliation to the University of Göttingen.
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A distal single nucleotide polymorphism alters long-range reguiavon of the PU-1 gene in acute myeloid leukemia
Steidl, U.; Steidl, C.; Ebralidze, A.; Chapuy, B. ; Han, H.-J.; Will, B. & Rosenbauer, F. et al. (2007)
Journal of Clinical Investigation, 117(9) pp. 2611-2620. DOI: https://doi.org/10.1172/JCI30525
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- Authors
- Steidl, Ulrich; Steidl, Christian; Ebralidze, Alexander; Chapuy, Bjoen ; Han, Hye-Jung; Will, Britta; Rosenbauer, Frank; Becker, Annegret; Wagner, Katharina; Koschmieder, Steffen; Kobayashi, Susumu; Costa, Daniel B.; Schuiz, Thomas; O'Brien, Karen B.; Verhaak, Roel G. W.; Dawel, Ruud; Haase, Detlef; Truemper, Lorenz H.; Krauter, Juergen; Kohwi-ShigematSU, Terumi; Griesinger, Frank; Tenen, Daniel G.
- Abstract
- Targeted disruption of a highly conserved distal enhancer reduces expression of the PU.1 transcription factor by 80% and leads to acute myeloid leukemia (AML) with frequent cytogenetic aberrations in mice. Here we identify a SNP within this element in humans that is more frequent in AML with a complex karyotype, leads to decreased enhancer activity, and reduces PU.1 expression in myeloid progenitors in a development-dependent manner. This SNP inhibits binding of the chromatin-remodeling transcriptional regulator special AT-rich sequence binding protein 1 (SATB1). Overexpression of SATB1 increased PU.1 expression, and siRNA inhibition of SATB1 downregulated PU.1 expression. Targeted disruption of the distal enhancer led to a loss of regulation of PU.1 by SATB1. Interestingly, disruption of SATB1 in mice led to a selective decrease of PU.1 RNA in specific progenitor types (granulocyte-macrophage and megakaryocyte-erythrocyte progenitors) and a similar effect was observed in AML samples harboring this SNP. Thus we have identified a SNP within a distal enhancer that is associated with a subtype of leukemia and exerts a deleterious effect through remote transcriptional dysregulation in specific progenitor subtypes.
- Issue Date
- 2007
- Status
- published
- Publisher
- Amer Soc Clinical Investigation Inc
- Journal
- Journal of Clinical Investigation
- ISSN
- 0021-9738
- Sponsor
- NCI NIH HHS [CA41456, R01 CA041456]