Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor

Rebecca Chan, Melissa B. Leedy, Veerendra Munugalavadla, Cara S. Voorhorst, Yanjun Li, Menggang Yu, Reuben Kapur

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)3737-3742
Number of pages6
JournalBlood
Volume105
Issue number9
DOIs
StatePublished - May 1 2005

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Granulocyte-Macrophage Colony-Stimulating Factor
Hypersensitivity
Mutation
Juvenile Myelomonocytic Leukemia
Macrophages
Extracellular Signal-Regulated MAP Kinases
Granulocyte-Macrophage Progenitor Cells
Chemical activation
Protein Tyrosine Phosphatases
Drug Design
Bone Marrow Cells
Bone
Stem Cells
Complementary DNA
Cells
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Hematology

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Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. / Chan, Rebecca; Leedy, Melissa B.; Munugalavadla, Veerendra; Voorhorst, Cara S.; Li, Yanjun; Yu, Menggang; Kapur, Reuben.

In: Blood, Vol. 105, No. 9, 01.05.2005, p. 3737-3742.

Research output: Contribution to journalArticle

Chan, Rebecca ; Leedy, Melissa B. ; Munugalavadla, Veerendra ; Voorhorst, Cara S. ; Li, Yanjun ; Yu, Menggang ; Kapur, Reuben. / Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. In: Blood. 2005 ; Vol. 105, No. 9. pp. 3737-3742.
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