A TET2 rs3733609 C/T genotype is associated with predisposition to the myeloproliferative neoplasms harboring JAK2(V617F) and confers a proliferative potential on erythroid lineages.
A TET2 rs3733609 C/T genotype is associated with predisposition to the myeloproliferative neoplasms harboring JAK2(V617F) and confers a proliferative potential on erythroid lineages.
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DOI：
10.18632/oncotarget.7072
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发表时间：
2016-02-23
期刊：
影响因子：
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通讯作者：
Zhang GS
中科院分区：
文献类型：
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作者：
Shen XH;Sun NN;Yin YF;Liu SF;Liu XL;Peng HL;Dai CW;Xu YX;Deng MY;Luo YY;Zheng WL;Zhang GS
JAK2基因座上常见的种系单核苷酸多态性（snp）与骨髓增生性肿瘤（MPN）有关。TERT中种系序列变异rs2736100 C与MPN发病风险相关，提示snp与MPN发病机制存在复杂关联。我们之前的研究（未发表的数据）表明，rs3733609 C/T基因型在一个中国家族性原发性骨髓纤维化的10 - 11易位2 （TET2）位点存在高频分布。在本研究中，我们评估了rs3733609 C/T基因型在jak2v617f阳性散发性MPN （n = 181）中的作用和临床意义。TET2 rs3733609 C/T基因型在jak2v617f阳性散发性MPN患者中的发病率（13.81%,25/181）高于正常对照（n = 236）（6.35%, 15/236），易患MPN(比值比(OR) = 2.361；P = 0.01)。与T/T基因型相比，rs3733609 C/T基因型MPN患者白细胞和血小板计数增加，血红蛋白浓度升高。rs3733609 C/T基因型MPN患者血栓事件发生率高于T/T基因型MPN患者（P < 0.01）。我们证实rs3733609 C/T基因型下调TET2 mRNA转录，其机制可能涉及CCAAT/增强子结合蛋白α (C/EBPA)与TET2 rs3733609 C/T位点之间相互作用的中断。TET2 rs3733609 C/T基因型刺激MPN患者的红细胞造血功能。总之，我们发现了一个新的遗传易感因子tet2 rs3733609 C/T变异与MPN的发展有关，表明该变异可能在一定程度上与MPN的发病和积累有关。
Common germline single-nucleotide polymorphisms (SNPs) at JAK2 locus have been associated with Myeloproliferative neoplasms (MPN). And, the germline sequence variant rs2736100 C in TERT is related to risk of MPN, suggesting a complex association between SNPs and the pathogenesis of MPN. Our previous study (unpublished data) showed that there was a high frequency distribution in rs3733609 C/T genotype at Ten-Eleven Translocation 2 (TET2) locus in one Chinese familial primary myelofibrosis. In the present study, we evaluate the role and clinical significance of rs3733609 C/T genotype in JAK2V617F-positive sporadic MPN (n = 181). TET2 rs3733609 C/T genotype had a higher incidence (13.81%; 25/181) in JAK2V617F-positive sporadic MPN patients than that in normal controls (n = 236) (6.35%; 15/236), which was predisposing to MPN (odds ratio(OR) = 2.361; P = 0.01). MPN patients with rs3733609 C/T genotype had increased leukocyte and platelets counts, elevated hemoglobin concentration in comparison with T/T genotype. Thrombotic events were more common in MPN patients with rs3733609 C/T than those with T/T genotype (P < 0.01). We confirmed that rs3733609 C/T genotype downregulated TET2 mRNA transcription, and the mechanism may be involved in a disruption of the interaction between CCAAT/enhancer binding protein alpha (C/EBPA) and TET2 rs3733609 C/T locus.TET2 rs3733609 C/T genotype stimulated the erythroid hematopoiesis in MPN patients. Altogether, we found a novel hereditary susceptible factor-TET2 rs3733609 C/T variant for the development of MPN, suggesting the variant may be partially responsible for the pathogenesis and accumulation of MPN.