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A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia
Ulrich Steidl, … , Frank Griesinger, Daniel G. Tenen
Ulrich Steidl, … , Frank Griesinger, Daniel G. Tenen
Published September 4, 2007
Citation Information: J Clin Invest. 2007;117(9):2611-2620. https://doi.org/10.1172/JCI30525.
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Research Article Oncology Article has an altmetric score of 3

A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia

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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.

Authors

Ulrich Steidl, Christian Steidl, Alexander Ebralidze, Björn Chapuy, Hye-Jung Han, Britta Will, Frank Rosenbauer, Annegret Becker, Katharina Wagner, Steffen Koschmieder, Susumu Kobayashi, Daniel B. Costa, Thomas Schulz, Karen B. O’Brien, Roel G.W. Verhaak, Ruud Delwel, Detlef Haase, Lorenz Trümper, Jürgen Krauter, Terumi Kohwi-Shigematsu, Frank Griesinger, Daniel G. Tenen

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Figure 2

The SNP in the first homology region of the URE of PU.1 leads to reduced enhancer activity.

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The SNP in the first homology region of the URE of PU.1 leads to reduced...
(A) Schematics of the reporter constructs utilized for stable transfections of U937 myeloid cells. Top: The proximal promoter of PU.1 in the pXP2 luciferase vector. Middle: The wild-type URE plus the proximal promoter of PU.1. Bottom: The SNP URE plus the proximal promoter of PU.1. The point mutation representing the SNP is indicated by a star. (B and C) Luciferase reporter assays after stable transfection of the above-described constructs into U937 cells shows reduced enhancer activity of the point-mutated URE. (B) The mean luciferase activity of 3 independent clones is displayed. Error bars indicate SD. (C) The mean luciferase activity of 3 independent cell pools is shown. Luciferase activity was normalized to transgene copy number as determined by Southern blotting. Error bars indicate SD. *P < 0.001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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