The DOI matches its Crossref record; 41 of the 41 references it cites were found in a registry or an index.
Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor
Open accessAbstract
Juvenile myelomonocytic leukemia (JMML) is a lethal disease of young children characterized by hypersensitivity of hematopoietic progenitors to granulocyte-macrophage colony-stimulating factor (GM-CSF). Mutations in PTPN11, which encodes the protein tyrosine phosphatase Shp-2, are common in JMML. We hypothesized that PTPN11 mutations induce hypersensitivity of hematopoietic progenitors to GM-CSF and confer increased GM-CSF–stimulated phospho–extracellular signal-regulated kinase (Erk) levels. To test this hypothesis, the wild-type (WT) and 3 mutant Ptpn11 cDNAs (E76K, D61V, and D61Y) were transduced into murine bone marrow cells to examine GM-CSF–stimulated granulocyte-macrophage colony-forming unit (CFU-GM) growth, macrophage progenitor proliferation, and activation of the Ras signaling pathway. Expression of the Shp-2 mutants induced progenitor cell hypersensitivity to GM-CSF compared with cells transduced with vector alone or WT Shp-2. Macrophage progenitors expressing the Shp-2 mutants displayed both basal and GM-CSF–stimulated hyperproliferation compared with cells transduced with vector alone or WT Shp-2. Consistently, macrophage progenitors transduced with the Shp-2 mutants demonstrated constitutively elevated phospho-Erk levels and sustained activation of phospho-Erk following GM-CSF stimulation compared with vector alone or WT Shp-2. These data support the hypothesis that PTPN11 mutations induce hematopoietic progenitor hypersensitivity to GM-CSF due to hyperactivation of the Ras signaling axis and provide a basis for the GM-CSF signaling pathway as a target for rational drug design in JMML.
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“Such activated SHP2 mutants also induce cytokine hypersensitivity in myeloid progenitors (15,18).”
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Protein tyrosine phosphatases: from genes, to function, to disease
Tonks, N. K. (2006) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2039 · Cited by 1,712
Ras oncogenes: split personalities
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Germline KRAS mutations cause Noonan syndrome
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Metadata
- Authors
- Chan, R. J., Leedy, M. B., Munugalavadla, V., Voorhorst, C. S., Li, Y., Yu, M., & Kapur, R.
- Affiliations
- Indiana University Indianapolis (US)
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2005-05-01
- Volume
- 105
- Issue
- 9
- Pages
- 3737-3742
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC1895012
- OpenAlex
- W1983831457
- Cited by
- 156
- References
- 40
- Citations by year
- 2026: 2 · 2024: 4 · 2023: 4 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 6 · 2016: 6 · 2015: 8 · 2014: 10 · 2013: 8 · 2012: 9
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL075816)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Hematology › Autoimmune and Inflammatory Disorders Research
- Keywords
- juvenile myelomonocytic leukemia, PTPN11 mutation, SHP2, GM-CSF, GM-CSF hypersensitivity, hematopoietic progenitor cells, macrophage progenitors, Ras signaling, ERK activation, CFU-GM, therapeutic target
- MeSH terms
- Animals, Bone Marrow Cells, Hematopoietic Stem Cells, Humans, Mice, Inbred C57BL, Phosphorylation, Transduction, Genetic, Signal Transduction, Leukemia, Myelomonocytic, Chronic, Granulocyte-Macrophage Colony-Stimulating Factor, Protein Tyrosine Phosphatases, Point Mutation, ras Proteins, Intracellular Signaling Peptides and Proteins, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 11
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