Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.
Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2.
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骨髓增生性肿瘤中的体细胞CALR突变与未突破的JAK2。
DOI：
10.1056/nejmoa1312542
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发表时间：
2013-12-19
期刊：
影响因子：
--
通讯作者：
Green AR
中科院分区：
文献类型：
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作者：
Nangalia J;Massie CE;Baxter EJ;Nice FL;Gundem G;Wedge DC;Avezov E;Li J;Kollmann K;Kent DG;Aziz A;Godfrey AL;Hinton J;Martincorena I;Van Loo P;Jones AV;Guglielmelli P;Tarpey P;Harding HP;Fitzpatrick JD;Goudie CT;Ortmann CA;Loughran SJ;Raine K;Jones DR;Butler AP;Teague JW;O'Meara S;McLaren S;Bianchi M;Silber Y;Dimitropoulou D;Bloxham D;Mudie L;Maddison M;Robinson B;Keohane C;Maclean C;Hill K;Orchard K;Tauro S;Du MQ;Greaves M;Bowen D;Huntly BJP;Harrison CN;Cross NCP;Ron D;Vannucchi AM;Papaemmanuil E;Campbell PJ;Green AR
许多骨髓增殖性肿瘤中都发生JAK2基因的体细胞突变，但JAK2非突变的骨髓增殖性肿瘤的分子发病机制尚不清楚，这些肿瘤的诊断仍然是一个挑战。我们对151例骨髓增生性肿瘤患者的样本进行了外显子组测序。编码钙网蛋白（CALR）的基因突变状态在另外1345例血液病、1517例其他癌症和550例对照中被评估。我们利用造血菌落建立了系统发育树。我们使用免疫荧光和流式细胞术评估钙网蛋白亚细胞定位。外显子组测序在151例患者中鉴定出1498个突变，真性红细胞增多症、原发性血小板增多症和骨髓纤维化患者的中位数分别为6.5、6.5和13.0个突变。在70 - 84%的JAK2非突变的骨髓增殖性肿瘤样本中发现了体细胞CALR突变，在8%的骨髓增生异常样本中发现了体细胞CALR突变，在其他骨髓癌样本中发现了体细胞CALR突变，而在其他癌症中没有发现体细胞CALR突变。共鉴定出148个CALR突变，包括19个不同的变体。突变位于外显子9，产生+1碱基对移码，这将导致具有新c端的突变蛋白。在内质网中观察到突变的钙调蛋白，但没有增加细胞表面或高尔基堆积。携带CALR突变的骨髓增殖性肿瘤患者比JAK2突变的患者血小板计数更高，血红蛋白水平更低。在造血干细胞和祖细胞中检测到CALR突变。克隆分析显示CALR突变发生在最早的系统发育节点，这一发现与它在一些患者中作为起始突变的作用一致。在大多数具有非突变JAK2的骨髓增殖性肿瘤患者中发现了内质网伴侣CALR的体细胞突变。（由凯肯德尔白血病基金和其他机构资助。）
Somatic mutations in the Janus kinase 2 gene (JAK2) occur in many myeloproliferative neoplasms, but the molecular pathogenesis of myeloproliferative neoplasms with nonmutated JAK2 is obscure, and the diagnosis of these neoplasms remains a challenge. We performed exome sequencing of samples obtained from 151 patients with myeloproliferative neoplasms. The mutation status of the gene encoding calreticulin (CALR) was assessed in an additional 1345 hematologic cancers, 1517 other cancers, and 550 controls. We established phylogenetic trees using hematopoietic colonies. We assessed calreticulin subcellular localization using immunofluorescence and flow cytometry. Exome sequencing identified 1498 mutations in 151 patients, with medians of 6.5, 6.5, and 13.0 mutations per patient in samples of polycythemia vera, essential thrombocythemia, and myelofibrosis, respectively. Somatic CALR mutations were found in 70 to 84% of samples of myeloproliferative neoplasms with nonmutated JAK2, in 8% of myelodysplasia samples, in occasional samples of other myeloid cancers, and in none of the other cancers. A total of 148 CALR mutations were identified with 19 distinct variants. Mutations were located in exon 9 and generated a +1 base-pair frameshift, which would result in a mutant protein with a novel C-terminal. Mutant calreticulin was observed in the endoplasmic reticulum without increased cell-surface or Golgi accumulation. Patients with myeloproliferative neoplasms carrying CALR mutations presented with higher platelet counts and lower hemoglobin levels than patients with mutated JAK2. Mutation of CALR was detected in hematopoietic stem and progenitor cells. Clonal analyses showed CALR mutations in the earliest phylogenetic node, a finding consistent with its role as an initiating mutation in some patients. Somatic mutations in the endoplasmic reticulum chaperone CALR were found in a majority of patients with myeloproliferative neoplasms with nonmutated JAK2. (Funded by the Kay Kendall Leukaemia Fund and others.)