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

J Clin Invest. 2007 Sep;117(9):2611-20. doi: 10.1172/JCI30525.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence
  • Cell Adhesion Molecules, Neuronal / genetics
  • Cell Adhesion Molecules, Neuronal / metabolism
  • Cell Line, Tumor
  • Down-Regulation
  • Gene Expression Regulation, Neoplastic*
  • Genome, Human / genetics
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / metabolism
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide / genetics*
  • Proto-Oncogene Proteins / deficiency
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins / metabolism
  • Receptors, Lymphocyte Homing / genetics
  • Receptors, Lymphocyte Homing / metabolism
  • Stem Cells / metabolism
  • Trans-Activators / deficiency
  • Trans-Activators / genetics*
  • Trans-Activators / metabolism

Substances

  • Cell Adhesion Molecules, Neuronal
  • Proto-Oncogene Proteins
  • Receptors, Lymphocyte Homing
  • STAB1 protein, human
  • Trans-Activators
  • proto-oncogene protein Spi-1