Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations
Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations
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DOI：
10.1016/j.ccr.2005.01.010
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发表时间：
2005-02-01
期刊：
影响因子：
50.3
通讯作者：
Neel, BG
中科院分区：
文献类型：
--
作者：
Mohi, MG;Williams, IR;Neel, BG
含有SH2的酪氨酸磷酸酶Shp2（PTPN11）是生长因子和细胞因子信号传导所必需的。种系Shp2突变导致努南综合征（NS），这与青少年粒单核细胞白血病（JMML）的风险增加有关。体细胞Shp2突变发生在散发性JMML和其他白血病中。我们发现与散发性白血病相关的Shp2突变体转化小鼠骨髓细胞，而NS突变体在该测定中的效力较低。转化需要Shp2和Shp2结合蛋白Gab2内的多个结构域，并且与Erk、Akt和Stat5途径的超活化相关。突变的Shp2转导的BM导致致命的JMML样疾病，或不太常见的淋巴细胞增生。Shp2突变体也引起果蝇的骨髓增生。Mek或Tor抑制剂有效抑制转化，提示JMML治疗的新方法。
The SH2-containing tyrosine phosphatase Shp2 (PTPN11) is required for growth factor and cytokine signaling. Germline Shp2 mutations cause Noonan Syndrome (NS), which is associated with increased risk of juvenile myelomonocytic leukemia (JMML). Somatic Shp2 mutations occur in sporadic JMML and other leukemias. We found that Shp2 mutants associated with sporadic leukemias transform murine bone marrow cells, whereas NS mutants are less potent in this assay. Transformation requires multiple domains within Shp2 and the Shp2 binding protein Gab2, and is associated with hyperactivation of the Erk, Akt, and Stat5 pathways. Mutant Shp2-transduced BM causes a fatal JMML-like disorder or, less commonly, lymphoproliferation. Shp2 mutants also cause myeloproliferation in Drosophila. Mek or Tor inhibitors potently inhibit transformation, suggesting new approaches to JMML therapy.