Ting-Juan Zhang1,2,3, Zi-Jun Xu2,3,4, Yu Gu1,2,3, Ji-Chun Ma2,3,4, Xiang-Mei Wen2,3,4, Wei Zhang1,2,3, Zhao-Qun Deng2,3,4, Jun Qian5,6,7, Jiang Lin8,9,10,11, Jing-Dong Zhou12,13,14. 1. Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. 2. Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China. 3. The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China. 4. Laboratory Center, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. 5. Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. qianjun0007@hotmail.com. 6. Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China. qianjun0007@hotmail.com. 7. The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China. qianjun0007@hotmail.com. 8. Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. 2651329493@qq.com. 9. Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China. 2651329493@qq.com. 10. The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China. 2651329493@qq.com. 11. Laboratory Center, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. 2651329493@qq.com. 12. Department of Hematology, Affiliated People's Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, People's Republic of China. zhoujingdong1989@qq.com. 13. Zhenjiang Clinical Research Center of Hematology, Zhenjiang, Jiangsu, People's Republic of China. zhoujingdong1989@qq.com. 14. The Key Lab of Precision Diagnosis and Treatment in Hematologic Malignancies of Zhenjiang City, Zhenjiang, Jiangsu, People's Republic of China. zhoujingdong1989@qq.com.
Abstract
BACKGROUND: Obesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated. RESULTS: In the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML. CONCLUSIONS: Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.
BACKGROUND: Obesity confers enhanced risk for multiple diseases including cancer. The DNA methylation alterations in obesity-related genes have been implicated in several human solid tumors. However, the underlying role and clinical implication of DNA methylation of obesity-related genes in acute myeloid leukemia (AML) has yet to be elucidated. RESULTS: In the discovery stage, we identified that DNA methylation-associated LEP expression was correlated with prognosis among obesity-related genes from the databases of The Cancer Genome Atlas. In the validation stage, we verified that LEP hypermethylation was a frequent event in AML by both targeted bisulfite sequencing and real-time quantitative methylation-specific PCR. Moreover, LEP hypermethylation, correlated with reduced LEP expression, was found to be associated with higher bone marrow blasts, lower platelets, and lower complete remission (CR) rate in AML. Importantly, survival analysis showed that LEP hypermethylation was significantly associated with shorter overall survival (OS) in AML. Moreover, multivariate analysis disclosed that LEP hypermethylation was an independent risk factor affecting CR and OS among non-M3 AML. By clinical and bioinformatics analysis, LEP may be also regulated by miR-517a/b expression in AML. CONCLUSIONS: Our findings indicated that the obesity-related gene LEP methylation is associated with LEP inactivation, and acts as an independent prognostic predictor in AML.
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