A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies
Open accessAbstract
p53—still hazy after all these years?: The gene encoding the p53 tumor suppressor protein is the most frequently mutated gene in human cancer. Yet decades after the gene's discovery, the biology of cancer-associated missense mutations in p53 is still being debated. Previous studies have suggested that missense mutations confer tumor-promoting functions to p53. Boettcher et al. conducted a detailed analysis of p53 missense mutations in human leukemia, drawing on methodologies including genome editing, a p53 saturation mutagenesis screen, mouse models, and clinical data (see the Perspective by Lane). They found no evidence that p53 missense mutations confer an oncogenic gain of function. Rather, the mutations exerted a dominant-negative effect that reduced the tumor suppressor activity of wild-type p53. Science , this issue p. 599 ; see also p. 539
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Loss of the TP53-WT allele confers an additional fitness advantage to TP53-sAML LSCs.
“Despite the known dominant negative and/or gain of function effect of certain TP53 mutations28,42, loss of the TP53-WT allele, a genetic event associated with a particularly dismal prognosis2, confers an additional fitness advantage to TP53-sAML LSCs.”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [28]
In the passage discussing mouse hematopoietic stem and progenitor cells (section labeled Abstract; page unavailable), cells with a TP53 missense mutation and no wild-type allele outcompeted cells retaining a wild-type allele after DNA damage. That supports an additional fitness advantage in that experimental setting, but the paper does not establish it for TP53-sAML leukemia stem cells. In the citing sentence, the citation is attached to the earlier statement about mutation effects, not directly to the LSC conclusion. (LLM, conf=0.88)
Experimental — accuracy not yet measuredSimilar findings were observed in TP53 knock-out or mutant isogenic MOLM13 cell lines.
“Similar findings were observed in TP53 knock-out or mutant isogenic MOLM13 cell lines (Extended Data Fig. 5m)28.”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [28]
Loss of the Trp53-WT allele confers an additional fitness advantage to Trp53-mutant HSPC following DNA damage.
“loss of the Trp53-WT allele confers an additional fitness advantage to Trp53-mutant HSPC following DNA damage as previously described28”
From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [28]
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- Authors
- Boettcher, S., Miller, P. G., Sharma, R., McConkey, M., Leventhal, M., Krivtsov, A. V., Giacomelli, A. O., Wong, W., Kim, J., Chao, S., Kurppa, K. J., Yang, X., Milenkowic, K., Piccioni, F., Root, D. E., Rücker, F. G., Flamand, Y., Neuberg, D., Lindsley, R. C., Jänne, P. A., Hahn, W. C., Jacks, T., Döhner, H., Armstrong, S. A., & Ebert, B. L.
- Affiliations
- Broad Institute (US)
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Universität Ulm (DE)
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
- Howard Hughes Medical Institute (US)
- Corresponding author
- Ebert, Benjamin L.
- ORCID
- Boettcher, Steffen
- Miller, Peter G.
- Sharma, Rohan
- McConkey, Marie
- Leventhal, Matthew
- Krivtsov, Andrei V.
- Giacomelli, Andrew O.
- Wong, Waihay
- Kim, Jesi
- Chao, Sherry
- Kurppa, Kari J.
- Yang, Xiaoping
- Milenkowic, Kirsten
- Piccioni, Federica
- Root, David E.
- Rücker, Frank G.
- Flamand, Yael
- Neuberg, Donna
- Lindsley, R. Coleman
- Hahn, William C.
- Jacks, Tyler
- Döhner, Hartmut
- Armstrong, Scott A.
- Ebert, Benjamin L.
- Venue
- Science
- Published
- 2019-08-09
- Volume
- 365
- Issue
- 6453
- Pages
- 599-604
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7327437
- OpenAlex
- W2968120913
- Cited by
- 441
- References
- 11
- Citations by year
- 2026: 56 · 2025: 57 · 2024: 73 · 2023: 75 · 2022: 62 · 2021: 52 · 2020: 53 · 2019: 12
- FWCI
- 18.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UTUPub (University of Turku) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- National Science Foundation
- Howard Hughes Medical Institute
- AstraZeneca
- Leukemia and Lymphoma Society
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Celgene
- Edward P. Evans Foundation
- Henry and Marilyn Taub Foundation
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (161026)
- Jane ja Aatos Erkon Säätiö
- Orionin Tutkimussäätiö
- Instrumentariumin Tiedesäätiö
- National Institutes of Health
- Foundation Medicine
- National Heart, Lung, and Blood Institute (R01HL082945, T32HL007623)
- National Human Genome Research Institute (T32HG002295)
- National Cancer Institute (U01CA176058, U01CA199253, P50CA206963, P01CA066996)
- National Institute of General Medical Sciences (R01GM038627)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Keywords
- TP53, p53, missense mutations, dominant negative effect, myeloid neoplasms, leukemia, tumor suppressor function, genome editing, mouse model
- MeSH terms
- Gain of Function Mutation, Animals, Genes, Dominant, Humans, Mice, Inbred C57BL, Selection, Genetic, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Mice, Knockout, K562 Cells, Mutation, Missense, Mice, CRISPR-Cas Systems
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