Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms
Phospho-STAT5 and phospho-Akt expression in chronic myeloproliferative neoplasms
复制标题
DOI：
10.1111/j.1365-2141.2009.07870.x
复制
发表时间：
2009-11-01
影响因子：
6.5
通讯作者：
Erber, Wendy N.
中科院分区：
文献类型：
--
作者：
Grimwade, Lizz F.;Happerfield, Lisa;Erber, Wendy N.
大多数骨髓增生性肿瘤（mpn）的特征是编码参与细胞信号传导的分子或受体的基因发生突变，最常见的是JAK2 V617F突变。这种突变通过组成性磷酸化导致下游信号通路的非配体激活。受影响的信号通路包括分别调控细胞存活和细胞凋亡的Janus激酶信号转导和转录激活因子（JAK-STAT）和磷脂酰肌苷-3激酶（PI3K）通路。对JAK2 V617F、JAK2外显子12、MPL外显子10和KIT D816V突变的MPN患者骨髓活检进行免疫细胞化学检测，制备phospo - stat5和phospo - akt单克隆抗体。JAK2 V617F突变与造血细胞中磷酸化STAT5和Akt水平显著升高相关，在巨核细胞中最为显著。相比之下，JAK2外显子12和MPL外显子10突变不影响磷酸化水平。在KIT D618V突变的全身性肥大细胞增多症中，肿瘤肥大细胞中磷酸化的STAT5和Akt的表达显著增加，而其他造血细胞的表达没有变化。JAK2 V617F在巨核细胞中与STAT5和Akt磷酸化上调相关，在其他造血细胞中也有较小程度的上调。骨髓环磷酰胺免疫细胞化学检测这些磷酸化蛋白可作为辅助诊断试验，阴性预测值高。
The majority of Myeloproliferative Neoplasms (MPNs) are characterised by mutations in genes encoding molecules or receptors involved in cell signalling, the most common being the JAK2 V617F mutation. This mutation leads to ligand-independent activation of downstream signalling pathways by constitutive phosphorylation. The signalling pathways affected include the Janus kinase-signal transducers and activators of transcription (JAK-STAT) and phosphotidylinositide-3 kinase (PI3K) pathways, which regulate cell survival and apoptosis respectively. Monoclonal antibodies to phospho-STAT5 and phospho-Akt were generated and assessed by immunocytochemistry on bone marrow biopsies of MPN patients with JAK2 V617F, JAK2 exon 12, MPL exon 10 and KIT D816V mutations. JAK2 V617F mutation was associated with significantly increased levels of phosphorylated STAT5 and Akt in haemopoietic cells, most marked in megakaryocytes. In contrast, JAK2 exon 12 and MPL exon 10 mutations did not affect the level of phosphorylation. In systemic mastocytosis with KIT D618V mutation there was significantly increased expression of phosphorylated STAT5 and Akt in neoplastic mast cells although there was no change in the expression in other haemopoietic cells. JAK2 V617F is associated with upregulated phosphorylation of STAT5 and Akt in megakaryocytes, and to a lesser extent in other haemopoietic cells. Immunocytochemistry of bone marrow trephines for these phosphoproteins can be used as a supplementary diagnostic test with a high negative predictive value.