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

Ulrich G. Steidl, Christian Steidl, Alexander Ebralidze, Björn Chapuy, Hye Jung Han, Britta Will, Frank Rosenbauer, Annegret Becker, Katharina Wagner, Steffen Koschmieder, Susumu Kobayashi, Daniel B. Costa, Thomas Schulz, Karen B. O'Brien, Roel G W Verhaak, Ruud Delwel, Detlef Haase, Lorenz Trümper, Jürgen Krauter, Terumi Kohwi-ShigematsuFrank Griesinger, Daniel G. Tenen

Research output: Contribution to journalArticle

84 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2611-2620
Number of pages10
JournalJournal of Clinical Investigation
Volume117
Issue number9
DOIs
StatePublished - Sep 4 2007
Externally publishedYes

Fingerprint

AT Rich Sequence
Acute Myeloid Leukemia
Single Nucleotide Polymorphism
Carrier Proteins
Genes
Megakaryocyte-Erythroid Progenitor Cells
Granulocyte-Macrophage Progenitor Cells
Chromatin Assembly and Disassembly
Karyotype
Chromosome Aberrations
Small Interfering RNA
Leukemia
Transcription Factors
Down-Regulation
RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. / Steidl, Ulrich G.; Steidl, Christian; Ebralidze, Alexander; Chapuy, Björn; Han, Hye Jung; Will, Britta; Rosenbauer, Frank; Becker, Annegret; Wagner, Katharina; Koschmieder, Steffen; Kobayashi, Susumu; Costa, Daniel B.; Schulz, Thomas; O'Brien, Karen B.; Verhaak, Roel G W; Delwel, Ruud; Haase, Detlef; Trümper, Lorenz; Krauter, Jürgen; Kohwi-Shigematsu, Terumi; Griesinger, Frank; Tenen, Daniel G.

In: Journal of Clinical Investigation, Vol. 117, No. 9, 04.09.2007, p. 2611-2620.

Research output: Contribution to journalArticle

Steidl, UG, Steidl, C, Ebralidze, A, Chapuy, B, Han, HJ, Will, B, Rosenbauer, F, Becker, A, Wagner, K, Koschmieder, S, Kobayashi, S, Costa, DB, Schulz, T, O'Brien, KB, Verhaak, RGW, Delwel, R, Haase, D, Trümper, L, Krauter, J, Kohwi-Shigematsu, T, Griesinger, F & Tenen, DG 2007, 'A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia', Journal of Clinical Investigation, vol. 117, no. 9, pp. 2611-2620. https://doi.org/10.1172/JCI30525
Steidl, Ulrich G. ; Steidl, Christian ; Ebralidze, Alexander ; Chapuy, Björn ; Han, Hye Jung ; Will, Britta ; Rosenbauer, Frank ; Becker, Annegret ; Wagner, Katharina ; Koschmieder, Steffen ; Kobayashi, Susumu ; Costa, Daniel B. ; Schulz, Thomas ; O'Brien, Karen B. ; Verhaak, Roel G W ; Delwel, Ruud ; Haase, Detlef ; Trümper, Lorenz ; Krauter, Jürgen ; Kohwi-Shigematsu, Terumi ; Griesinger, Frank ; Tenen, Daniel G. / A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia. In: Journal of Clinical Investigation. 2007 ; Vol. 117, No. 9. pp. 2611-2620.
@article{3a75e1cfe451454aa90ef41c42cea66c,
title = "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 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.",
author = "Steidl, {Ulrich G.} and Christian Steidl and Alexander Ebralidze and Bj{\"o}rn Chapuy and Han, {Hye Jung} and Britta Will and Frank Rosenbauer and Annegret Becker and Katharina Wagner and Steffen Koschmieder and Susumu Kobayashi and Costa, {Daniel B.} and Thomas Schulz and O'Brien, {Karen B.} and Verhaak, {Roel G W} and Ruud Delwel and Detlef Haase and Lorenz Tr{\"u}mper and J{\"u}rgen Krauter and Terumi Kohwi-Shigematsu and Frank Griesinger and Tenen, {Daniel G.}",
year = "2007",
month = "9",
day = "4",
doi = "10.1172/JCI30525",
language = "English (US)",
volume = "117",
pages = "2611--2620",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "9",

}

TY - JOUR

T1 - A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia

AU - Steidl, Ulrich G.

AU - Steidl, Christian

AU - Ebralidze, Alexander

AU - Chapuy, Björn

AU - Han, Hye Jung

AU - Will, Britta

AU - Rosenbauer, Frank

AU - Becker, Annegret

AU - Wagner, Katharina

AU - Koschmieder, Steffen

AU - Kobayashi, Susumu

AU - Costa, Daniel B.

AU - Schulz, Thomas

AU - O'Brien, Karen B.

AU - Verhaak, Roel G W

AU - Delwel, Ruud

AU - Haase, Detlef

AU - Trümper, Lorenz

AU - Krauter, Jürgen

AU - Kohwi-Shigematsu, Terumi

AU - Griesinger, Frank

AU - Tenen, Daniel G.

PY - 2007/9/4

Y1 - 2007/9/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=34848850741&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34848850741&partnerID=8YFLogxK

U2 - 10.1172/JCI30525

DO - 10.1172/JCI30525

M3 - Article

C2 - 17694175

AN - SCOPUS:34848850741

VL - 117

SP - 2611

EP - 2620

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

ER -