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Cited by 159Protein Tyrosine PhosphatasesImmunodeficiency and Autoimmune DisordersAutoimmune and Inflammatory Disorders Research

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

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Chan, Rebecca J., Leedy, Melissa B., Munugalavadla, Veerendra, Voorhorst, Cara S., Li, Yanjun, Yu, Menggang, Kapur, Reuben·2005·Blood
DOI 10.1182/blood-2004-10-4002PMC PMC1895012
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Abstract

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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  1. Mongomery DC. Design and Analysis of Experiments. 4th ed. Hoboken, NJ: John Wiley & Sons; 1997.

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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)
ORCID
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
DOI
10.1182/blood-2004-10-4002
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
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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