Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms
Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms
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DOI：
10.1056/nejmoa1311347
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发表时间：
2013-12-19
影响因子：
158.5
通讯作者：
Kralovics, Robert
中科院分区：
文献类型：
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作者：
Klampfl, Thorsten;Gisslinger, Heinz;Kralovics, Robert
大约50%至60%的原发性血小板增多症或原发性骨髓纤维化患者携带JAK2基因突变，另外5%至10%的患者具有血小板生成素受体基因（MPL）的激活突变。到目前为止，在剩余的30 - 45%的患者中没有发现特异性的分子标记物。方法：我们对6例没有JAK2或MPL突变的原发性骨髓纤维化患者进行了全外显子组测序，以鉴定体细胞获得性突变。编码钙网蛋白的CALR重测序随后在髓系肿瘤患者队列中进行。结果在所有进行全外显子测序的患者中均检测到CALR外显子9的体细胞插入或缺失。对来自骨髓增殖性肿瘤患者的1107个样本进行重测序显示真性红细胞增多症中没有CALR突变。在原发性血小板增多症和原发性骨髓纤维化中，CALR突变和JAK2和MPL突变是相互排斥的。在JAK2或MPL未突变的原发性血小板增多症或原发性骨髓纤维化患者中，67%的原发性血小板增多症患者检测到CALR突变，88%的原发性骨髓纤维化患者检测到CALR突变。共有36种类型的插入或缺失被确定，它们都导致相同的替代阅读框移码，并在突变的钙网蛋白中产生新的c端肽。由于信号换能器和转录激活因子5 （STAT5）以未知机制激活，最常见的CALR缺失的过表达导致体外细胞因子非依赖性生长。与JAK2突变的患者相比，CALR突变的患者血栓形成的风险更低，总生存期更长。结论：大多数与JAK2或MPL改变无关的原发性血小板增多症或原发性骨髓纤维化患者携带CALR体细胞突变。与JAK2 V617F突变患者相比，这些患者的临床病程更为缓慢。（由MPN研究基金会和意大利癌症研究协会资助）
Background Approximately 50 to 60% of patients with essential thrombocythemia or primary myelofibrosis carry a mutation in the Janus kinase 2 gene (JAK2), and an additional 5 to 10% have activating mutations in the thrombopoietin receptor gene (MPL). So far, no specific molecular marker has been identified in the remaining 30 to 45% of patients.MethodsWe performed whole-exome sequencing to identify somatically acquired mutations in six patients who had primary myelofibrosis without mutations in JAK2 or MPL. Resequencing of CALR, encoding calreticulin, was then performed in cohorts of patients with myeloid neoplasms.ResultsSomatic insertions or deletions in exon 9 of CALR were detected in all patients who underwent whole-exome sequencing. Resequencing in 1107 samples from patients with myeloproliferative neoplasms showed that CALR mutations were absent in polycythemia vera. In essential thrombocythemia and primary myelofibrosis, CALR mutations and JAK2 and MPL mutations were mutually exclusive. Among patients with essential thrombocythemia or primary myelofibrosis with nonmutated JAK2 or MPL, CALR mutations were detected in 67% of those with essential thrombocythemia and 88% of those with primary myelofibrosis. A total of 36 types of insertions or deletions were identified that all cause a frameshift to the same alternative reading frame and generate a novel C-terminal peptide in the mutant calreticulin. Overexpression of the most frequent CALR deletion caused cytokine-independent growth in vitro owing to the activation of signal transducer and activator of transcription 5 (STAT5) by means of an unknown mechanism. Patients with mutated CALR had a lower risk of thrombosis and longer overall survival than patients with mutated JAK2.ConclusionsMost patients with essential thrombocythemia or primary myelofibrosis that was not associated with a JAK2 or MPL alteration carried a somatic mutation in CALR. The clinical course in these patients was more indolent than that in patients with the JAK2 V617F mutation. (Funded by the MPN Research Foundation and Associazione Italiana per la Ricerca sul Cancro.)