Essential role of Jun family transcription factors in PU.1 knockdown–induced leukemic stem cells
Abstract
Knockdown of the transcription factor PU.1 (encoded by Sfpi1) leads to acute myeloid leukemia (AML) in mice. We examined the transcriptome of preleukemic hematopoietic stem cells (HSCs) in which PU.1 was knocked down (referred to as 'PU.1-knockdown HSCs') to identify transcriptional changes preceding malignant transformation. Transcription factors c-Jun and JunB were among the top-downregulated targets. Restoration of c-Jun expression in preleukemic cells rescued the PU.1 knockdown-initiated myelomonocytic differentiation block. Lentiviral restoration of JunB at the leukemic stage led to loss of leukemic self-renewal capacity and prevented leukemia in NOD-SCID mice into which leukemic PU.1-knockdown cells were transplanted. Examination of human individuals with AML confirmed the correlation between PU.1 and JunB downregulation. These results delineate a transcriptional pattern that precedes leukemic transformation in PU.1-knockdown HSCs and demonstrate that decreased levels of c-Jun and JunB contribute to the development of PU.1 knockdown-induced AML by blocking differentiation and increasing self-renewal. Therefore, examination of disturbed gene expression in HSCs can identify genes whose dysregulation is essential for leukemic stem cell function and that are targets for therapeutic interventions.
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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 [15]
Development of myeloid leukemia in mice with decreased PU.1 expression is dependent on Jun.
“The development of myeloid leukemia in mice that have decreased expression of PU.1 is dependent on Jun [27].”
From The Transcription Factor PU.1 Regulates γδ T Cell Homeostasis (2011) · cites this paper as [27]
Complete genetic ablation of PU.1 can yield a profound differentiation block that graduates to an AML-like phenotype.
“While complete genetic ablation of PU.1 can yield a profound differentiation block that graduates to an AML-like phenotype (Steidl et al., 2006)”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Steidl et al., 2006
Several other transcriptional regulators interact with PU.1, including AP-1 family transcription factors.
“Moreover, several other transcriptional regulators interact with PU.1, including AP-1 family transcription factors (Steidl et al., 2006; Boasman et al., 2019; Zhao et al., 2022).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Steidl et al., 2006
The AP-1 factors c-Jun and JunB are critical interacting partners with PU.1 that also regulate myeloid differentiation, including PU.1 expression.
“Indeed, the AP-1 factors c-Jun and JunB are also critical interacting partners with PU.1 that also regulate myeloid differentiation (including PU.1 expression) (Steidl et al., 2006; Raghav et al., 2018; Zhao et al., 2022).”
From PU.1 is required to restrain myelopoiesis during chronic inflammatory stress (2023) · cites this paper as Steidl et al., 2006
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References 50 · Cited by 184
- Authors
- Steidl, U., Rosenbauer, F., Verhaak, R. G. W., Gu, X., Ebralidze, A., Otu, H. H., Klippel, S., Steidl, C., Bruns, I., Costa, D. B., Wagner, K., Aivado, M., Kobbe, G., Valk, P. J. M., Passegué, E., Libermann, T. A., Delwel, R., & Tenen, D. G.
- Affiliations
- Harvard University (US)
- Erasmus MC (NL)
- Beth Israel Deaconess Medical Center (US)
- Yeditepe University (TR)
- University of Göttingen (DE)
- Heinrich Heine University Düsseldorf (DE)
- Corresponding author
- Tenen, Daniel G
- ORCID
- Venue
- Nature Genetics
- Published
- 2006-10-15
- Volume
- 38
- Issue
- 11
- Pages
- 1269-1277
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2122742344
- Cited by
- 184
- References
- 50
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 2 · 2023: 14 · 2022: 4 · 2021: 9 · 2020: 5 · 2019: 12 · 2018: 7 · 2017: 9 · 2016: 4 · 2015: 5 · 2014: 11 · 2013: 20 · 2012: 11
- FWCI
- 9.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- GRO (submittedVersion)
- Funders
- Lymphoma Research Foundation
- National Institutes of Health
- National Cancer Institute (CA 41456, R01CA041456)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- PU.1, acute myeloid leukemia, leukemia stem cells, hematopoietic stem cells, c-Jun, JunB, self-renewal, transcriptome, gene knockdown, NOD/SCID xenotransplantation
- MeSH terms
- Proto-Oncogene Protein Spi-1, Animals, Cell Differentiation, Cell Transformation, Neoplastic, Granulocytes, Hematopoietic Stem Cells, Humans, Monocytes, Proto-Oncogene Proteins, Transcription, Genetic, Transduction, Genetic, Leukemia, Myeloid, Acute, Trans-Activators, Down-Regulation, Mice, SCID, Mice, Inbred NOD, Proto-Oncogene Proteins c-jun, Mice, Knockout, Hematopoietic Stem Cell Transplantation, Mice
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