A distal single nucleotide polymorphism alters long-range regulation of the PU.1 gene in acute myeloid leukemia
Open accessAbstract
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.
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Moderate PU.1 inhibition is common in AML patients.
“yet moderate PU.1 inhibition is common in AML patients”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [16]
The Introduction says moderate decreases in PU.1 can contribute to malignant transformation, and the Discussion reports lower PU.1 expression in a specific cell population from AML patients carrying the studied SNP. Neither passage establishes that moderate PU.1 inhibition is common across AML patients; the Discussion says the SNP was not more frequent in all AML patients than in controls. Page numbers were not provided in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSeveral AML-typic mutations, such as NPM1c, FLT3-ITD/TDK, or AML1-ETO, moderately compromise the regulation or function of PU.1.
“Several AML-typic mutations, such as NPM1c, FLT3-ITD/TDK, or AML1-ETO, moderately compromise the regulation or function of PU.1 (19–22)”
From PU.1-Dependent Enhancer Inhibition Separates <i>Tet2</i> -Deficient Hematopoiesis from Malignant Transformation (2022) · cites this paper as [21]
The Discussion (page unavailable) states that AML1-ETO inhibits PU.1 protein function in patients with AML. It does not address NPM1c or FLT3-ITD/TDK, or characterize AML1-ETO’s effect as moderate; the Introduction discusses moderate decreases in PU.1 levels generally, not for those mutations. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAnimal numbers were chosen based on previous experiences with transplanting hematopoietic cells of the parental mouse strain.
“Animal numbers were chosen based on previous experiences with transplanting hematopoietic cells of the parental mouse strain9, 16.”
From Minimal PU.1 reduction induces a preleukemic state and promotes development of acute myeloid leukemia (2015) · cites this paper as [16]
The Methods section (page unavailable) describes the mouse strains and approval of mouse experiments, but does not explain how animal numbers were chosen. A search for transplantation, parental mouse strain, and sample-size rationale found no passage addressing the claim. (LLM, conf=0.72)
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References 51 · Cited by 114
Research works printed but not linked: 2
- Walter, M.J., et al. 2005. Reduced PU.1 expres- sion causes myeloid progenitor expansion and increased leukemia penetrance in mice express- ing PML-RARalpha. Proc. Natl. Acad. Sci. U. S. A. 102:12513-12518.
- Manz, M.G., Miyamoto, T., Akashi, K., and Weiss- man, I.L. 2002. Prospective isolation of human clo- nogenic common myeloid progenitors. Proc. Natl. Acad. Sci. U. S. A. 99:11872-11877.
- Authors
- Steidl, U., Steidl, C., Ebralidze, A., Chapuy, B., Han, H.-J., Will, B., Rosenbauer, F., Becker, A., Wagner, K., Koschmieder, S., Kobayashi, S., Costa, D. B., Schulz, T., O’Brien, K. B., Verhaak, R. G. W., Delwel, R., Haase, D., Trümper, L., Krauter, J., Kohwi-Shigematsu, T., Griesinger, F., & Tenen, D. G.
- Affiliations
- Harvard University (US)
- BC Cancer Agency (CA)
- Lawrence Berkeley National Laboratory (US)
- University of Göttingen (DE)
- Erasmus MC (NL)
- Medizinische Hochschule Hannover (DE)
- Corresponding author
- Tenen, Daniel G.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2007-09-04
- Volume
- 117
- Issue
- 9
- Pages
- 2611-2620
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1937499
- OpenAlex
- W2081736209
- Cited by
- 114
- References
- 51
- Citations by year
- 2026: 1 · 2024: 2 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 5 · 2019: 6 · 2018: 1 · 2017: 6 · 2016: 6 · 2015: 9 · 2014: 7 · 2013: 7 · 2012: 13
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- GRO (submittedVersion)
- OpenAgrar (submittedVersion)
- Funders
- Lymphoma Research Foundation
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- National Cancer Institute (CA 41456, R01CA041456)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- PU.1, acute myeloid leukemia, single nucleotide polymorphisms, distal enhancers, long-range gene regulation, SATB1, chromatin remodeling, transcriptional dysregulation, myeloid progenitor cells, complex karyotype, enhancer disruption, CFU-GM, megakaryocyte-erythrocyte progenitors
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Base Sequence, Humans, Molecular Sequence Data, Proto-Oncogene Proteins, Stem Cells, Leukemia, Myeloid, Acute, Trans-Activators, Down-Regulation, Cell Adhesion Molecules, Neuronal, Genome, Human, Gene Expression Regulation, Neoplastic, Receptors, Lymphocyte Homing, Mice, Knockout, Polymorphism, Single Nucleotide, Cell Line, Tumor, Mice
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