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

• Published in: Blood 2005-05, Vol.105 (9), p.3737-3742
• Main Authors: Chan, Rebecca J., Leedy, Melissa B., Munugalavadla, Veerendra, Voorhorst, Cara S., Li, Yanjun, Yu, Menggang, Kapur, Reuben
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Bone Marrow Cells - metabolism; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases - metabolism; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells - drug effects; Humans; Intracellular Signaling Peptides and Proteins; Leukemia, Myelomonocytic, Chronic - etiology; Leukemia, Myelomonocytic, Chronic - metabolism; Leukemia, Myelomonocytic, Chronic - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Mice; Mice, Inbred C57BL; Neoplasia; Phosphorylation; Point Mutation; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatases - genetics; ras Proteins - metabolism; Signal Transduction; Transduction, Genetic
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-10-4002

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.