Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients
Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients
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DOI：
10.1002/ajh.23743
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发表时间：
2014-08-01
影响因子：
12.8
通讯作者：
Passamonti, Francesco
中科院分区：
文献类型：
--
作者：
Tefferi, Ayalew;Wassie, Emnet A.;Passamonti, Francesco
CALR（钙网蛋白）是JAK 2之后的第二大突变基因，在原发性血小板增多症（ET）中。ET中的突变CALR是由外显子9缺失或插入引起的移码突变的结果; 1型，52-bp缺失（p.L367fs*46）和2型，5-bp TTGTC插入（p.K385fs*47）变体占这些突变的80%以上。本研究共纳入1027例患者，分为试验组（n = 402）和验证组（n = 625）。在测试队列中的402名ET患者中，227名（57%）携带JAK 2、11名（3%）骨髓增生性白血病病毒癌基因（MPL）和114名（28%）CALR突变; 12%对于所有三种突变都是野生型（即，三重否定）。在114例CALR突变患者中，51例（45%）显示1型和44例（39%）显示2型变异;与突变JAK 2相比，这两种变异均与血小板升高、血红蛋白和白细胞计数降低相关。然而，男性仅与1型（P = 0.005）和2型（P = 0.001）变异年龄较小。值得注意的是，2型CALR突变患者的血小板计数显著高于1型CALR突变患者（P = 0.03），并且在包括111名CALR突变ET患者的验证队列中验证了特定观察结果（P = 0.002）。这些发现，再加上最近的证明，在巨核细胞中的突变体和野生型CALR的优先表达，表明血小板生成的CALR变体的差异影响。(C)2014 Wiley Periodicals，Inc.
CALR (calreticulin) trails JAK2 as the second most mutated gene in essential thrombocythemia (ET). Mutant CALR in ET is a result of frameshift mutations, caused by exon 9 deletions or insertions; type-1, 52-bp deletion (p.L367fs*46), and type-2, 5-bp TTGTC insertion (p.K385fs*47) variants constitute more than 80% of these mutations. The current study includes a total of 1027 patients divided into test (n = 402) and validation (n = 625) cohorts. Among the 402 ET patients in the test cohort, 227 (57%) harbored JAK2, 11 (3%) Myeloproliferative leukemia virus oncogene (MPL), and 114 (28%) CALR mutations; 12% were wild-type for all three mutations (i.e., triple-negative). Among the 114 patients with CALR mutations, 51 (45%) displayed type-1 and 44 (39%) type-2 variants; compared to mutant JAK2, both variants were associated with higher platelet and lower hemoglobin and leukocyte counts. However, male sex was associated with only type-1 (P = 0.005) and younger age with type-2 (P = 0.001) variants. Notably, platelet count was significantly higher in type-2 vs. type-1 CALR-mutated patients (P = 0.03) and the particular observation was validated in the validation cohort that included 111 CALR-mutated ET patients (P = 0.002). These findings, coupled with the recent demonstration of preferential expression of mutant and wild-type CALR in megakaryocytes, suggest differential effects of CALR variants on thrombopoiesis. (C) 2014 Wiley Periodicals, Inc.