Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor
Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor
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DOI：
10.1182/blood-2004-10-4002
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发表时间：
2005-05-01
期刊：
影响因子：
20.3
通讯作者：
Kapur, R
中科院分区：
文献类型：
--
作者：
Chan, RJ;Leedy, MB;Kapur, R
幼年型粒单核细胞白血病（juvenile myelomonocytic leukemia，JMML）是一种以粒细胞-巨噬细胞集落刺激因子（granulocyte-macrophage colony-stimulating factor，GM-CSF）对造血祖细胞的超敏反应为特征的致死性疾病。编码蛋白酪氨酸磷酸酶Shp-2的PTPN 11突变在JMML中很常见。我们假设PTPN 11突变诱导造血祖细胞对GM-CSF的超敏反应，并增加GM-CSF刺激的磷酸化细胞外信号调节激酶（Erk）水平。为了验证这一假设，将野生型（WT）和3种突变型Ptpn 11 cDNA（E76 K、D 61 V和D 61 Y）导入小鼠骨髓细胞，以检查GM-CSF刺激的粒细胞-巨噬细胞集落形成单位（CFU-GM）生长、巨噬细胞祖细胞增殖和Ras信号传导途径的激活。与用单独的载体或WT Shp-2转导的细胞相比，Shp-2突变体的表达诱导祖细胞对GM-CSF的超敏性。与单独用载体或WT Shp-2转导的细胞相比，表达Shp-2突变体的巨噬细胞祖细胞显示基础和GM-CSF刺激的过度增殖。一致地，与单独的载体或WT Shp-2相比，用Shp-2突变体转导的巨噬细胞祖细胞表现出组成性升高的磷酸化Erk水平和GMCSF刺激后磷酸化Erk的持续活化。这些数据支持了PTPN 11突变诱导造血祖细胞对GMCSF超敏反应的假设，这是由于Ras信号轴的过度激活，并为GM-CSF信号通路作为JMML中合理药物设计的靶点提供了基础。
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, D61 V, and D61 Y) were tranduced 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 GMCSF stimulation compared with vector alone or WT Shp-2. These data support the hypothesis that PTPN11 mutations induce hematopoietic progenitor hypersensitivity to GMCSF 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.