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.
Steidl
Ulrich
U
Harvard Institutes of Medicine, Harvard Medical School, and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA.
Steidl
Christian
C
Ebralidze
Alexander
A
Chapuy
Björn
B
Han
Hye-Jung
HJ
Will
Britta
B
Rosenbauer
Frank
F
Becker
Annegret
A
Wagner
Katharina
K
Koschmieder
Steffen
S
Kobayashi
Susumu
S
Costa
Daniel B
DB
Schulz
Thomas
T
O'Brien
Karen B
KB
Verhaak
Roel G W
RG
Delwel
Ruud
R
Haase
Detlef
D
Trümper
Lorenz
L
Krauter
Jürgen
J
Kohwi-Shigematsu
Terumi
T
Griesinger
Frank
F
Tenen
Daniel G
DG
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
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
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