A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia
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.
|Persistent URL||dx.doi.org/10.1172/JCI30525, hdl.handle.net/1765/35205|
Steidl, U., Ebralidze, A., Chapuy, B., Han, H.-J., Will, B., Rosenbauer, F., … Tenen, D.G.. (2007). A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. Journal of Clinical Investigation, 117(9), 2611–2620. doi:10.1172/JCI30525