Mohi M Golam, Williams Ifor R, Dearolf Charles R, Chan Gordon, Kutok Jeffery L, Cohen Sarah, Morgan Kelly, Boulton Christina, Shigematsu Hirokazu, Keilhack Heike, Akashi Koichi, Gilliland D Gary, Neel Benjamin G
Cancer Biology Program, Department of Medicine, Beth Israel Deaconess Medical Center, 77 Avenue Louis Pasteur, NRB-1030, Boston, Massachusetts 02115, USA.
Cancer Cell. 2005 Feb;7(2):179-91. doi: 10.1016/j.ccr.2005.01.010.
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.
含SH2结构域的酪氨酸磷酸酶Shp2（PTPN11）是生长因子和细胞因子信号传导所必需的。种系Shp2突变会导致努南综合征（NS），这与青少年骨髓单核细胞白血病（JMML）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突变体可转化小鼠骨髓细胞，而在该检测中，NS突变体的效力较低。转化需要Shp2内的多个结构域以及Shp2结合蛋白Gab2，并且与Erk、Akt和Stat5途径的过度激活有关。突变型Shp2转导的骨髓会导致致命的JMML样疾病，或较少见的淋巴增殖。Shp2突变体在果蝇中也会导致骨髓增殖。Mek或Tor抑制剂可有效抑制转化，这提示了JMML治疗的新方法。
