Progression to polythythemia vera from familial thrombocytosis with germline JAK2 R867Q mutation
Progression to polythythemia vera from familial thrombocytosis with germline JAK2 R867Q mutation
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伴种系 JAK2 R867Q 突变的家族性血小板增多症进展为真性红细胞增多症
DOI：
10.1007/s00277-017-3209-1
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发表时间：
2018
影响因子：
3.5
通讯作者：
Chiba Shigeru
中科院分区：
文献类型：
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作者：
Maie Koichiro;Yokoyama Yasuhisa;Yano Yoko;Kato Takayasu;Nannya Yasuhito;Ogawa Seishi;Noguchi Masayuki;Sakata-Yanagimoto Mamiko;Chiba Shigeru
一名 31 岁女性（患者 5），有 25 年血小板增多病史，被转诊至我院（图 1a）。她的血红蛋白水平正常。她的父亲（患者 3）也表现出轻度血小板增多症，但血红蛋白水平较高，促红细胞生成素水平正常至较低。他的血小板持续偏高，直到56岁，血红蛋白水平一直在16.5克/分升左右波动。但从59岁开始，他的血红蛋白水平明显偏高（>18克/分升），而血小板计数却逐渐下降（图1b）。他的血细胞比容水平也很高（53.2%），平均红细胞体积在正常范围内（95 fl）。他有轻度脾肿大。白细胞分类计数在正常范围内（带状中性粒细胞，2.5%；分段中性粒细胞，54.5%；淋巴细胞，25.5%；单核细胞，4%；嗜酸性粒细胞，3%；嗜碱性粒细胞，1%）。他的促红细胞生成素水平为 3.0–18.4 mIU/ml（正常范围为 9.1–32.8）。 62 岁时对 3 号患者进行的骨髓活检显示，细胞增多，伴有全骨髓增生，血管周围区域网状蛋白网络松散（图 1 c-d）。骨髓细胞遗传学正常（46，XY [20]）。这些结果表明，患者 3 最初表现出 ET 样表型，但现在符合 PV 标准。患者3和5的一些家庭成员，包括一名0岁婴儿，也表现出明显的血小板增多症（图1a），这增加了家族性MPN的可能性。通过对中性粒细胞进行靶向 DNA 测序，我们探索了 3 号和 5 号患者的骨髓恶性肿瘤中涉及的 67 个基因 [7]，并在这两个病例中发现了杂合 JAK2 R867Q 突变。我们还在患者 3 中发现了 TET2 S271X 的 stopgain 突变，等位基因频率为 5%，而在患者 5 中没有相关体细胞突变。接下来，我们使用中性粒细胞（来自患者 1 至 7）和口腔拭子（来自患者 1 至 8）对目前的家庭成员进行桑格测序。所有受影响的成员（患者 3、5、6 和 8）的基因中均存在杂合 JAK2 R867Q 突变。
A 31-year-old woman (patient 5) with a 25-year history of thrombocytosis was referred to our hospital (Fig. 1 a). Her hemoglobin level was normal. Her father (patient 3) also showed mild thrombocytosis but had high-hemoglobin levels with normal to low erythropoietin levels. His platelets had been persistently high, and his hemoglobin levels fluctuated around 16.5 g/dl until he was 56. However, since the age of 59, his hemoglobin levels have been apparently high (> 18 g/dl) while platelet counts have been gradually decreasing (Fig. 1 b). His hematocrit levels were also high (53.2%), and mean corpuscular volume was within normal range (95 fl). He had mild splenomegaly. The differential count of his white blood cells was within normal range (Band neutrophils, 2.5%; Segmented neutrophils, 54.5%; Lymphocytes, 25.5%; Monocytes, 4%; Eosinophils, 3%; Basophils, 1%). His erythropoietin level was 3.0–18.4 mIU/ml (normal range, 9.1–32.8). Bone marrow biopsy of patient 3 performed at the age of 62 showed hypercellularity with panmyelosis and loose network of reticulin in perivascular areas (Fig. 1 c–d). The cytogenetics of bone marrow was normal (46, XY [20]). These results suggest that patient 3 showed ET-like phenotype at first but now meets the criteria for PV. Some family members of patients 3 and 5, including a 0-year-old infant, also showed marked thrombocytosis (Fig. 1 a), which raised the possibility of familial MPN. Using targeted DNA sequencing in neutrophils, we explored 67 genes that are implicated in myeloid malignancies for patients 3 and 5 [7] and found heterozygous JAK2 R867Q mutations in both cases. We also found a stopgain mutation of TET2 S271X with an allele frequency of 5% in patient 3 and no relevant somatic mutations in patient 5. Next, we performed Sanger sequencing using neutrophils (from patients 1 to 7) and buccal swabs (from patients 1 to 8) in the present family members. All affected members (patients 3, 5, 6, and 8) had the heterozygous JAK2 R867Q mutations in their