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Let-7a-3 hypomethylation is associated with favorable/intermediate karyotypes but not with survival in acute myeloid leukemia

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Tumor Biology

Abstract

Aberrant methylation of let-7a-3 promoter has been observed in various malignancies. However, the clinical relevance of let-7a-3 methylation remains poorly known in acute myeloid leukemia (AML). This study was to investigate the let-7a-3 methylation status and to explore its clinical significance in AML. let-7a-3 promoter was significantly hypomethylated in AML patients compared to controls (median 4.51 vs 0.49) (P = 0.0003). Receiver operating characteristic curve (ROC) analysis discriminated all patients or cytogenetically normal patients from controls with an areas under the ROC curve (AUC) of 0.737 or 0.783, respectively (P < 0.001). Patients with favorable/intermediate karyotypes had significantly higher let-7a-3 unmethylation than controls. Patients with DNMT3A mutations had a trend of high level of let-7a-3 unmethylation than did those with wild-type DNMT3A (median 6.76 vs 3.66, P = 0.096). There was no significant difference in overall survival between patients with and without hypomethylated let-7a-3 (median 12 vs 5 months, P = 0.103). No correlation was observed between the level of let-7a-3 expression and let-7a-3 unmethylation in AML samples (R = 0.197, P = 0.150). However, the level of let-7a-3 expression was increased in a dose-dependent manner in THP-1 line treated with 5-aza-dC, while the methylation density of let-7a-3 promoter decreased with 5-aza-dC dose. Our findings suggest that let-7a-3 hypomethylation is associated with favorable and intermediate karyotypes but not a prognostic predictor for AML patients. Let-7a-3 expression may be partially regulated by promoter methylation.

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Acknowledgments

This study was supported by the National Natural Science foundation of China (81270630, 81172592), 333 Project of Jiangsu Province (BRA2013136), Science and Technology Special Project in Clinical Medicine of Jiangsu Province (BL2012056), Science and Technology Infrastructure Program of Zhenjiang (SS2012003), Social Development Foundation of Zhenjiang (SH2013042, SH2013082, SH2014044), Key Medical Talent Program of Zhenjiang City, and Jiangsu Government Scholarship for Overseas Studies.

Conflict of interest

None.

Compliance with ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Affiliated People’ Hospital of Jiangsu University Ethics Committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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    Authors and Affiliations

    1. Department of Hematology, Affiliated People’s Hospital of Jiangsu University, 8 Dianli Rd, 212002, Zhenjiang, Jiangsu, People’s Republic of China

      Xiao-wen Zhu, De-hong Wu, Jing Yang, Lei Yang, Ying-ying Zhang & Jun Qian

    2. Laboratory Center, Affiliated People’s Hospital of Jiangsu University, 8 Dianli Rd, 212002, Zhenjiang, Jiangsu, People’s Republic of China

      Dong-ming Yao, Xiang-mei Wen, Hong Guo, Zhao-qun Deng, Wei Qian & Jiang Lin

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    1. Xiao-wen Zhu
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    Correspondence to Wei Qian, Jiang Lin or Jun Qian.

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    Xiao-wen Zhu, Dong-ming Yao and De-hong Wu contributed equally to this work.

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    Zhu, Xw., Yao, Dm., Wu, Dh. et al. Let-7a-3 hypomethylation is associated with favorable/intermediate karyotypes but not with survival in acute myeloid leukemia. Tumor Biol. 37, 491–501 (2016). https://doi.org/10.1007/s13277-015-3734-2

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