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

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 developmentdependent 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.

Allelic Imbalance at rs6983267 Suggests Selection of the Risk Allele in Somatic Colorectal Tumor Evolution

“…Identification of target genes for such variations is possible by studying the correlation of the genotype and expression of nearby genes, whereas effects of trans-acting variants are more difficult to discover. Recently, regulatory SNPs in nongenic regions underlying complex human diseases have been identified (18,19). The well-established role of MYC in colorectal neoplasia makes it the most promising candidate gene at 8q24.21.…”

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

“…SATB1 binds to special AT-rich sequences and its expression appears to be a positive regulator of PU.1 expression requiring an intact URE. 83 Mice deleted of the Satb1 gene showed lower levels of PU.1 in progenitor cells but not in the terminally differentiated progeny indicating that Satb1 may cooperate in early stages of myeloid development. 83 Satb1 À/À mice, unlike URE À/À mutants, do not develop myeloid leukemia.…”

“…83 Mice deleted of the Satb1 gene showed lower levels of PU.1 in progenitor cells but not in the terminally differentiated progeny indicating that Satb1 may cooperate in early stages of myeloid development. 83 Satb1 À/À mice, unlike URE À/À mutants, do not develop myeloid leukemia. However, it should be noted that Satb1 À/À mice die prematurely (early postnatal) and the limited life-span may not be sufficient for any myeloid leukemias to develop.…”

“…Interestingly, a single nucleotide polymorphism within the URE has been identified, which significantly diminishes binding of SATB1. The single nucleotide polymorphism is frequently associated with poor prognosis of human leukemias 83 and strongly suggests that the altered URE enhancer activity is coupled with reduced PU.1 levels within developing myeloid progenitors thereby contributing to the pathogenesis of human myeloid leukemias.…”

An Evolutionarily Conserved TNF-α–Responsive Enhancer in the Far Upstream Region of Human CCL2 Locus Influences Its Gene Expression

“…For example, it has recently been shown that a distal single nucleotide polymorphism alters long-range regulation of PU.1 gene in acute myeloid leukemia through modulation of binding of the chromatin-remodeling transcriptional regulator SATB1 (76). As interindividual variation in CCL2 expression and its role in disease pathogenesis are well recognized (8,77,78), we analyzed the ECRs identified in this study for presence of single nucleotide polymorphisms.…”