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.
authors: Harvard Institutes of Medicine, Harvard Medical School, and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
authors: Ulrich
authors: U
authors: Steidl
authors: Christian
authors: C
authors: Steidl
authors: Alexander
authors: A
authors: Ebralidze
authors: Björn
authors: B
authors: Chapuy
authors: Hye-Jung
authors: HJ
authors: Han
authors: Britta
authors: B
authors: Will
authors: Frank
authors: F
authors: Rosenbauer
authors: Annegret
authors: A
authors: Becker
authors: Katharina
authors: K
authors: Wagner
authors: Steffen
authors: S
authors: Koschmieder
authors: Susumu
authors: S
authors: Kobayashi
authors: Daniel B
authors: DB
authors: Costa
authors: Thomas
authors: T
authors: Schulz
authors: Karen B
authors: KB
authors: O'Brien
authors: Roel G W
authors: RG
authors: Verhaak
authors: Ruud
authors: R
authors: Delwel
authors: Detlef
authors: D
authors: Haase
authors: Lorenz
authors: L
authors: Trümper
authors: Jürgen
authors: J
authors: Krauter
authors: Terumi
authors: T
authors: Kohwi-Shigematsu
authors: Frank
authors: F
authors: Griesinger
authors: Daniel G
authors: DG
authors: Tenen
mesh_terms: D000818:Animals; D001483:Base Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D011518:Proto-Oncogene Proteins; D016201:Receptors, Lymphocyte Homing; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C449926:STAB1 protein, human
references: Nat Genet. 2002 Dec;32(4):666-9
references: 12402038
references: Blood. 2005 Sep 1;106(5):1519-24
references: 15914558
references: Nat Rev Cancer. 2003 Feb;3(2):89-101
references: 12563308
references: Nat Genet. 2003 May;34(1):42-51
references: 12692553
references: Nat Genet. 2003 Dec;35(4):341-8
references: 14608356
references: Nat Genet. 2004 Jun;36(6):624-30
references: 15146183
references: Blood. 2004 Jul 1;104(1):81-8
references: 15016651
references: Nat Genet. 2004 Jul;36(7):725-31
references: 15184899
references: N Engl J Med. 2004 Aug 12;351(7):657-67
references: 15306667
references: Cell. 2004 Oct 29;119(3):431-43
references: 15507213
references: Cell. 1992 Aug 21;70(4):631-45
references: 1505028
references: Science. 1994 Sep 9;265(5178):1573-7
references: 8079170
references: EMBO J. 1996 Oct 15;15(20):5647-58
references: 8896458
references: Blood. 1997 Jul 15;90(2):489-519
references: 9226149
references: Mol Cell Biol. 1997 Sep;17(9):5275-87
references: 9271405
references: Biochemistry. 1997 Oct 7;36(40):12005-10
references: 9340009
references: Blood. 1998 Oct 1;92(7):2322-33
references: 9746770
references: Blood. 2004 Dec 1;104(12):3437-44
references: 15304397
references: Cancer Cell. 2004 Dec;6(6):587-96
references: 15607963
references: J Exp Med. 2005 Jan 17;201(2):221-31
references: 15657291
references: J Immunol. 2005 Feb 1;174(3):1525-31
references: 15661912
references: N Engl J Med. 2005 Feb 24;352(8):786-92
references: 15728811
references: J Biol Chem. 2002 Sep 13;277(37):33968-77
references: 12121983
references: Blood. 2005 Apr 15;105(8):3330-9
references: 15618465
references: J Hum Genet. 2005;50(3):133-8
references: 15744455
references: Proc Natl Acad Sci U S A. 2005 Aug 30;102(35):12513-8
references: 16113082
references: Trends Cell Biol. 2005 Sep;15(9):494-501
references: 16084092
references: Gene. 2005 Oct 10;359:44-52
references: 16102917
references: Nat Genet. 2006 Jan;38(1):27-37
references: 16311598
references: Blood. 2006 Apr 15;107(8):3330-8
references: 16352814
references: Science. 2006 May 26;312(5777):1215-7
references: 16728641
references: Nat Genet. 2006 Nov;38(11):1269-77
references: 17041602
references: Nat Genet. 2006 Nov;38(11):1278-88
references: 17057718
references: Genes Dev. 2000 Mar 1;14(5):521-35
references: 10716941
references: Nature. 2000 Mar 9;404(6774):193-7
references: 10724173
references: Blood. 2000 Dec 15;96(13):4075-83
references: 11110676
references: Br J Haematol. 2001 Jan;112(1):118-26
references: 11167792
references: Blood. 2001 Nov 15;98(10):2958-65
references: 11698277
references: Blood. 2002 Mar 15;99(6):2037-44
references: 11877277
references: Blood. 2002 Aug 1;100(3):998-1007
references: 12130514
references: J Pathol. 2002 Sep;198(1):115-20
references: 12210071
references: Nature. 2002 Oct 10;419(6907):641-5
references: 12374985
references: Mol Cell Biol. 2005 Apr;25(7):2832-45
references: 15767686
references: Proc Natl Acad Sci U S A. 2002 Sep 3;99(18):11872-7
references: 12193648
references: Blood. 2002 Dec 15;100(13):4325-36
references: 12393746
references: J Exp Med. 2005 May 2;201(9):1487-502
references: 15867096
references: Genes Chromosomes Cancer. 2005 Jul;43(3):227-38
references: 15846790
references: Hum Genet. 2005 Jun;117(1):16-26
references: 15806396
references: Oncogene. 2005 May 19;24(22):3678-83
references: 15750630
references: Blood. 2005 Sep 1;106(5):1590-600
references: 15914556
references: Blood. 2003 Jan 1;101(1):270-7
references: 12393465