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

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Official URL:https://doi.org/10.1172/JCI30525
PubMed:View item in PubMed
Creators Name:Steidl, U. and Steidl, C. and Ebralidze, A. and Chapuy, B. and Han, H.J. and Will, B. and Rosenbauer, F. and Becker, A. and Wagner, K. and Koschmieder, S. and Kobayashi, S. and Costa, D.B. and Schulz, T. and OBrien, K.B. and Verhaak, R.G.W. and Delwel, R. and Haase, D. and Truemper, L. and Krauter, J. and Kohwi-Shigematsu, T. and Griesinger, F. and Tenen, D.G.
Journal Title:Journal of Clinical Investigation
Journal Abbreviation:J Clin Invest
Volume:117
Number:9
Page Range:2611-2620
Date:4 September 2007
Keywords:Acute Myeloid Leukemia, Base Sequence, Down-Regulation, Human Genome, Lymphocyte Homing Receptors, Molecular Sequence Data, Neoplastic Gene Expression Regulation, Neuronal Cell Adhesion Molecules, Proto-Oncogene Proteins, Single Nucleotide Polymorphism, Stem Cells, Trans-Activators, Tumor Cell Line, Animals, Mice
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.
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Item Type:Article

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