Suppressor screen in Mpl -/- mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling
Open accessAbstract
Genetic screens in lower organisms, particularly those that identify modifiers of preexisting genetic defects, have been used successfully to order components of complex signaling pathways. To date, similar suppressor screens have not been used in vertebrates. To define the molecular pathways regulating platelet production, we have executed a large-scale modifier screen with genetically thrombocytopenic Mpl - / - mice by using N -ethyl- N -nitrosourea mutagenesis. Here we show that mutations in the c-Myb gene cause a myeloproliferative syndrome and supraphysiological expansion of megakaryocyte and platelet production in the absence of thrombopoietin signaling. This screen demonstrates the utility of large-scale N -ethyl- N -nitrosourea mutagenesis suppressor screens in mice for the simultaneous discovery and in vivo validation of targets for therapeutic discovery in diseases for which mouse models are available.
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Genetic modifier screens are commonly applied to identify genes that act in developmental or biochemical pathways in fruit flies, worms, and bacteria, but this approach is rare in the mouse.
“Genetic modifier screens are commonly applied to identify genes that act in developmental or biochemical pathways in fruit flies, worms, and bacteria10; however, this approach is rare in the mouse11,12.”
From A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome (2013) · cites this paper as [11]
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- Authors
- Carpinelli, M. R., Hilton, D. J., Metcalf, D., Antonchuk, J. L., Hyland, C. D., Mifsud, S. L., Di Rago, L., Hilton, A. A., Willson, T. A., Roberts, A. W., Ramsay, R. G., Nicola, N. A., & Alexander, W. S.
- Affiliations
- Walter and Eliza Hall Institute of Medical Research (AU)
- The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville VIC 3052, Australia; and The Peter MacCallum Cancer Centre, St. Andrews Place, East Melbourne VIC 3002, Australia
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2004-04-07
- Volume
- 101
- Issue
- 17
- Pages
- 6553-6558
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC404083
- OpenAlex
- W2104427970
- Cited by
- 179
- References
- 34
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2022: 1 · 2021: 5 · 2020: 3 · 2019: 6 · 2018: 8 · 2017: 8 · 2016: 9 · 2015: 6 · 2014: 6 · 2013: 6 · 2012: 6
- FWCI
- 10.87
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Keywords
- MYB, thrombopoietin signaling, megakaryopoiesis, megakaryocytes, myeloproliferative syndromes, thrombocytopenia, suppressor screen, N-ethyl-N-nitrosourea mutagenesis
- MeSH terms
- Animals, Blood Platelets, Female, Flow Cytometry, Homozygote, Male, Mice, Inbred C57BL, Mutation, Neoplasm Proteins, Phenotype, Proto-Oncogene Proteins, Thrombopoietin, Signal Transduction, Genes, Suppressor, Receptors, Cytokine, Mice, Knockout, Cell Lineage, Genes, myb, Mice, Receptors, Thrombopoietin
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