Department of Hematology and Rheumatology, Kagoshima University Hospital, Kagoshima, Japan.
Division of Hematology and Rheumatology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan.
Int J Hematol. 2019 Nov;110(5):584-590. doi: 10.1007/s12185-019-02725-8. Epub 2019 Aug 19.
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.
本研究旨在阐明非典型 JAK2 突变 JAK2-T875N 的作用，该突变是通过对一名有疑似 ET 家族史的原发性血小板增多症（ET）患者的外显子组测序发现的。对外周血单核细胞和口腔拭子来源的基因组 DNA 进行了全外显子组测序。采用 Sanger 测序对变异进行了确认。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（Erk、STATs）的影响。转染了携带 V617F 或 T875N 突变的 JAK2 cDNA 的 293T 细胞显示出磷酸化 JAK2 和 Erk 水平的升高。通过启动子测定证实了增强的 STAT3 和 STAT5 活性。JAK2-T875N 转导的 Ba/F3 细胞在没有 IL-3 刺激的情况下表现出增强的细胞生长。据我们所知，这是首例有 ET 家族史的 JAK2-T875N 突变引起的 ET 病例，伴有血小板增多和脑梗死。
