文章：

CALR突变状态可识别出不同亚型的原发性血小板增多症，这些亚型显示出不同的表达谱

CALR mutational status identifies different disease subtypes of essential thrombocythemia showing distinct expression profiles

原文发布日期：2017-12-08

DOI: 10.1038/s41408-017-0010-2

类型: Article

开放获取: 是

英文摘要：

Polycythemia vera (PV) and essential thrombocythemia (ET) are Philadelphia-negative myeloproliferative neoplasms (MPNs) characterized by erythrocytosis and thrombocytosis, respectively. Approximately 95% of PV and 50–70% of ET patients harbor the V617F mutation in the exon 14 of JAK2 gene, while about 20–30% of ET patients carry CALRins5 or CALRdel52 mutations. These ET CALR-mutated subjects show higher platelet count and lower thrombotic risk compared to JAK2-mutated patients. Here, we showed that CALR-mutated and JAK2V617F-positive CD34+ cells display different gene and miRNA expression profiles. Indeed, we highlighted several pathways differentially activated between JAK2V617F- and CALR-mutated progenitors, i.e., mTOR, MAPK/PI3K, and MYC pathways. Furthermore, we unveiled that the expression of several genes involved in DNA repair, chromatin remodeling, splicing, and chromatid cohesion are decreased in CALR-mutated cells. According to the low risk of thrombosis in CALR-mutated patients, we also found the downregulation of several genes involved in thrombin signaling and platelet activation. As a whole, these data support the model that CALR-mutated ET could be considered as a distinct disease entity from JAK2V617F-positive MPNs and may provide the molecular basis supporting the different clinical features of these patients.

摘要翻译： 

真性红细胞增多症（PV）和原发性血小板增多症（ET）均属费城染色体阴性骨髓增殖性肿瘤（MPNs），分别以红细胞增多和血小板增多为特征。约95%的PV患者及50-70%的ET患者携带JAK2基因外显子14的V617F突变，而约20-30%的ET患者存在CALRins5或CALRdel52突变。与JAK2突变患者相比，携带CALR突变的ET患者表现为更高血小板计数和更低血栓风险。本研究表明，CALR突变与JAK2V617F阳性CD34+细胞呈现不同的基因和miRNA表达谱。我们进一步揭示JAK2V617F与CALR突变祖细胞之间存在多条差异激活通路，包括mTOR、MAPK/PI3K和MYC信号通路。此外，发现CALR突变细胞中参与DNA修复、染色质重塑、RNA剪接和染色单体黏连的多个基因表达下调。与CALR突变患者低血栓风险相符，我们还观察到涉及凝血酶信号传导和血小板活化的多个基因表达下降。总体而言，这些数据支持将CALR突变型ET视为独立于JAK2V617F阳性MPNs的疾病实体，并为其不同临床特征提供了分子基础依据。

原文链接：

CALR mutational status identifies different disease subtypes of essential thrombocythemia showing distinct expression profiles