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| Item Type: | Article |
|---|---|
| Title: | A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia |
| Creators Name: | Steidl, U., Steidl, C., Ebralidze, A., Chapuy, B., Han, H.J., Will, B., Rosenbauer, F., Becker, A., Wagner, K., Koschmieder, S., Kobayashi, S., Costa, D.B., Schulz, T., OBrien, K.B., Verhaak, R.G.W., Delwel, R., Haase, D., Truemper, L., Krauter, J., Kohwi-Shigematsu, T., Griesinger, F. and Tenen, D.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. |
| 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 |
| Source: | Journal of Clinical Investigation |
| ISSN: | 0021-9738 |
| Publisher: | American Society for Clinical Investigation |
| Volume: | 117 |
| Number: | 9 |
| Page Range: | 2611-2620 |
| Date: | 4 September 2007 |
| Official Publication: | https://doi.org/10.1172/JCI30525 |
| PubMed: | View item in PubMed |
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