A TET2 rs3733609 C/T genotype is associated with predisposition to the myeloproliferative neoplasms harboring JAK2V617F and confers a proliferative potential on erythroid lineages

Xiao-Hui Shen,Hong-Ling Peng,Wen-Li Zheng,Xiao-Liu Liu,Ya-Fei Yin,Yun-Ya Luo,Chong-Wen Dai,Ming-Yang Deng,Nan-Nan Sun,Guang-Sen Zhang,Yun-Xiao Xu,Su-Fang Liu

doi:10.18632/oncotarget.7072

Xiao-Hui Shen, Hong-Ling Peng + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.7072

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Journal: Oncotarget	Publication Date: Jan 29, 2016
Citations: 29	License type: cc-by

Affiliation: Central South University, South University

Abstract

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 Our previous study (unpublished data) showed that there was a high frequency distribution in rs3733609 C/T genotype at Ten-Eleven Translocation 2 (TET2) locus in one Chinese familial primary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.

Highlights

The most common BCR-ABL negative Myeloproliferative neoplasms (MPN) includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [1]
To determine whether rs3733609 C/T genotype was associated with the predisposition to sporadic MPN, we analyzed the distribution of Ten-Eleven Translocation 2 (TET2) rs3733609 C/T genotype using PCR-direct sequencing in 181 MPN patients with JAK2V617F-positive and 236 healthy controls
Our results showed that the C/T genotype was enriched in the MPN group compared to healthy controls (P = 0.01; Odd Ratio (OR) = 2.361; 95% Confidence Interval (CI) = 1.206–4.624), suggesting that TET2 rs3733609 C/T genotype was associated with a predisposition to sporadic MPNs

Summary

Introduction

The most common BCR-ABL negative MPN includes polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) [1]. JAK2V617F mutation is present in the majority of PV patients, and about half of ET and PMF cases [3,4,5], while MPL and CALR mutations are exclusively detected in ET and PMF patients, suggesting the presence of one or more genes variants is associated with risk of MPN [6,7,8,9,10]. The germline sequence variant rs2736100 C in TERT contributes to sporadic and familial MPN has been reported [14, 15]. These germline variations at JAK2 and TERT loci may explain part of the population risk for developing MPN. The presence of host-modifying genetic factors or concomitant mutations in other genes, such as TET2, ASXL1, could modulate the MPN phenotype and contribute to the pathogenesis of MPN [16,17,18]

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