Hematopoietic Stem Cell Expansion Precedes the Generation of Committed Myeloid Leukemia-Initiating Cells in C/EBPα Mutant AML
Open accessAbstract
We here use knockin mutagenesis in the mouse to model the spectrum of acquired CEBPA mutations in human acute myeloid leukemia. We find that C-terminal C/EBPalpha mutations increase the proliferation of long-term hematopoietic stem cells (LT-HSCs) in a cell-intrinsic manner and override normal HSC homeostasis, leading to expansion of premalignant HSCs. However, such mutations impair myeloid programming of HSCs and block myeloid lineage commitment when homozygous. In contrast, N-terminal C/EBPalpha mutations are silent with regards to HSC expansion, but allow the formation of committed myeloid progenitors, the templates for leukemia-initiating cells. The combination of N- and C-terminal C/EBPalpha mutations incorporates both features, accelerating disease development and explaining the clinical prevalence of this configuration of CEBPA mutations.
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CEBPA knockout or mutation is reported to cause a myeloid to erythroid lineage switch with increased expression of GATA1, and GATA1 interacts with and inhibits p53.
“CEBPA knockout or mutation is reported to cause a myeloid to erythroid lineage switch with increased expression of GATA1 (refs. 29,30) and, in addition, GATA1 interacts with and inhibits p53 (ref. 45).”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [30]
The CEBPA/GATA1 expression ratio, an important transcription factor balance that affects erythroid versus myeloid differentiation in leukemia, is disrupted by TP53 mutation.
“These observations suggest that the CEBPA/GATA1 expression ratio, an important transcription factor balance that affects erythroid versus myeloid differentiation in leukemia29,30, is disrupted by TP53 mutation.”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [30]
Cites
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A clonogenic common myeloid progenitor that gives rise to all myeloid lineages
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Rodriguez-Meira, A., Norfo, R., Wen, S., Chédeville, A. L., Rahman, H., O’Sullivan, J., Wang, G., Louka, E., Kretzschmar, W. W., Paterson, A., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01480-1 · Cited by 158 · see citing works
Self-citationPundhir, S., Bratt Lauridsen, F. K., Schuster, M. B., Jakobsen, J. S., Ge, Y., Schoof, E. M., Rapin, N., Waage, J., Hasemann, M. S., & Porse, B. T. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.05.012 · Cited by 77 · see citing works
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- Authors
- Bereshchenko, O., Mancini, E., Moore, S., Bilbao, D., Månsson, R., Luc, S., Grover, A., Jacobsen, S. E. W., Bryder, D., & Nerlov, C.
- Affiliations
- European Molecular Biology Laboratory (IT)
- Lund University (SE)
- University of Oxford (GB)
- Corresponding author
- Nerlov, Claus
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 16
- Issue
- 5
- Pages
- 390-400
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W1977427229
- Cited by
- 147
- References
- 3
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 16 · 2020: 7 · 2019: 9 · 2018: 4 · 2017: 7 · 2016: 6 · 2015: 13 · 2014: 12 · 2013: 13 · 2012: 13
- FWCI
- 8.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- 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
- acute myeloid leukemia, hematopoietic stem cells, leukemia-initiating cells, HSC expansion, myeloid lineage commitment, myeloid progenitor cells, C-terminal mutations, N-terminal mutation, HSC homeostasis
- MeSH terms
- Animals, Cell Cycle, Cell Line, Cell Transformation, Neoplastic, Hematopoietic Stem Cells, Humans, Leukemia, Myeloid, Acute, Gene Expression Regulation, Leukemic, Mice, Knockout, Hematopoietic Stem Cell Transplantation, CCAAT-Enhancer-Binding Protein-alpha, Cell Growth Processes, Mice
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