文章：

在Gata1low骨髓纤维化小鼠模型中，血小板生成素/MPL轴被激活，并与RPS14缺陷特征相关

The thrombopoietin/MPL axis is activated in the Gata1low mouse model of myelofibrosis and is associated with a defective RPS14 signature

原文发布日期：2017-06-16

DOI: 10.1038/bcj.2017.51

类型: Original Article

开放获取: 是

英文摘要：

Myelofibrosis (MF) is characterized by hyperactivation of thrombopoietin (TPO) signaling, which induces a RPS14 deficiency that de-regulates GATA1 in megakaryocytes by hampering its mRNA translation. As mice carrying the hypomorphic Gata1low mutation, which reduces the levels of Gata1 mRNA in megakaryocytes, develop MF, we investigated whether the TPO axis is hyperactive in this model. Gata1low mice contained two times more Tpo mRNA in liver and TPO in plasma than wild-type littermates. Furthermore, Gata1low LSKs expressed levels of Mpl mRNA (five times greater than normal) and protein (two times lower than normal) similar to those expressed by LSKs from TPO-treated wild-type mice. Gata1low marrow and spleen contained more JAK2/STAT5 than wild-type tissues, an indication that these organs were reach of TPO-responsive cells. Moreover, treatment of Gata1low mice with the JAK inhibitor ruxolitinib reduced their splenomegaly. Also in Gata1low mice activation of the TPO/MPL axis was associated with a RSP14 deficiency and a discordant microarray ribosome signature (reduced RPS24, RPS26 and SBDS expression). Finally, electron microscopy revealed that Gata1low megakaryocytes contained poorly developed endoplasmic reticulum with rare polysomes. In summary, Gata1low mice are a bona fide model of MF, which recapitulates the hyperactivation of the TPO/MPL/JAK2 axis observed in megakaryocytes from myelofibrotic patients.

摘要翻译： 

骨髓纤维化（MF）的特征是血小板生成素（TPO）信号过度激活，该信号通过阻碍GATA1的mRNA翻译诱导RPS14缺陷，从而导致巨核细胞中GATA1失调。由于携带低效Gata1low突变的小鼠（该突变降低巨核细胞中Gata1 mRNA水平）会发展成MF，我们研究了该模型中TPO轴是否过度活跃。Gata1low小鼠肝脏中Tpo mRNA含量及血浆中TPO含量均为野生型同窝小鼠的两倍。此外，Gata1low LSK细胞表达的Mpl mRNA水平（较正常高五倍）和蛋白水平（较正常低两倍）与TPO处理的野生型小鼠LSK细胞表达水平相似。Gata1low小鼠骨髓和脾脏所含JAK2/STAT5量高于野生型组织，表明这些器官富含TPO应答细胞。此外，用JAK抑制剂鲁索替尼治疗Gata1low小鼠可减轻其脾肿大。同样在Gata1low小鼠中，TPO/MPL轴的激活与RSP14缺陷及不一致的微阵列核糖体特征（RPS24、RPS26和SBDS表达降低）相关。最后，电子显微镜显示Gata1low巨核细胞的内质网发育不良，多聚核糖体稀少。总之，Gata1low小鼠是骨髓纤维化的真实模型，重现了在骨髓纤维化患者巨核细胞中观察到的TPO/MPL/JAK2轴过度激活现象。

原文链接：

The thrombopoietin/MPL axis is activated in the Gata1low mouse model of myelofibrosis and is associated with a defective RPS14 signature