Essential thrombocytosis attributed to JAK2-T875N germline mutation
Essential thrombocytosis attributed to JAK2-T875N germline mutation
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DOI：
10.1007/s12185-019-02725-8
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发表时间：
2019-11-01
影响因子：
2.1
通讯作者：
Ishitsuka, Kenji
中科院分区：
文献类型：
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作者：
Yoshimitsu, Makoto;Hachiman, Miho;Ishitsuka, Kenji
本研究的目的是阐明非典型 JAK2 突变 JAK2-T875N 的作用，该突变是通过外显子组测序在一名有疑似 ET 家族史的原发性血小板增多症 (ET) 患者中发现的。对外周血单核细胞和口腔拭子来源的基因组 DNA 进行全外显子组测序。进行桑格测序以确认该变异。我们使用 JAK2-T875N 转染或转导的细胞系评估了突变对 JAK2 活性和下游信号传导（Erk、STAT）的功能。用携带 V617F 或 T875N 突变的 JAK2 cDNA 转染的 293T 细胞显示磷酸化 JAK2 和 Erk 水平增加。通过启动子测定证实了 STAT3 和 STAT5 活性的增强。 JAK2-T875N 转导的 Ba/F3 细胞在没有 IL-3 刺激的情况下显示出细胞生长增加。据了解，这是首例JAK2-T875N突变导致的ET病例，且有血小板增多症和脑梗塞家族史。
The aim of this study was to elucidate the role of a non-canonical JAK2 mutation JAK2-T875N, which was identified by exome sequencing in a patient with essential thrombocytosis (ET) who had a family history of suspecting ET. Whole exome sequencing was performed on peripheral blood mononuclear cells and buccal swab-derived genomic DNA. Sanger sequencing was performed to confirm the variant. We evaluated the function of the mutation on JAK2 activity and downstream signaling (Erk, STATs) using JAK2-T875N-transfected or transduced cell lines. 293T cells transfected with JAK2 cDNA carrying V617F or T875N mutations showed increased levels of phosphorylated JAK2 and Erk. Enhanced STAT3 and STAT5 activity was confirmed by promoter assay. JAK2-T875N-transduced Ba/F3 cells showed increased cellular growth without IL-3 stimulation. To our knowledge, this is the first case of ET caused by JAK2-T875N mutation with a family history of thrombocytosis and cerebral infarction.