Methylation‐associated DOK1 and DOK2 down‐regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia

作者：Pin-fang He, Zi‐jun Xu, Jing‐dong Zhou, Xi-xi Li, Wei Zhang, Dehong Wu, Zhihui Zhang, Xinyue Lian, Xinyu Yao, Zhaoqun Deng, Jiang Lin, Jun Qian · 发表于：Journal of Cellular Physiology · 年份：2017 · DOI：10.1002/jcp.26271 · 被引用次数：18 · 研究领域：Acute Myeloid Leukemia Research、Epigenetics and DNA Methylation、Myeloproliferative Neoplasms: Diagnosis and Treatment

DOK-1 and DOK-2 (DOK1/2) are closely related members of downstream of tyrosine kinase (DOK) family genes, which are found to be frequently rearranged in several hematopoietic cancers. However, the clinical implications of DOK1/2 in acute myeloid leukemia (AML) remain largely unknown. To investigate the clinical significance, real-time quantitative PCR (RQ-PCR) was carried out to detect DOK1/2 expressions in 125 de novo AML patients and 28 healthy controls. Real-time quantitative methylation-specific PCR (RQ-MSP) and bisulfite sequencing PCR (BSP) were applied to detect DOK1/2 methylation level and density. DOK1/2 expressions were significantly down-regulated in AML patients. The promoters of DOK1/2 were highly hypermethylated and negatively correlated with DOK1/2 expressions in AML patients. In addition, we also confirmed that DOK1/2 expressions could be restored by DOK1/2 demethylation using 5-aza-2'-deoxycytidine in leukemia cell line THP-1. Survival analyses showed that low-expressed DOK1/2 were associated with markedly shorter overall survival and leukemia free survival in both whole-cohort AML and non-M3 AML patients. Multivariate analyses further revealed that DOK1/2 were act as independent prognostic factors in AML patients. These findings indicate that decreased DOK1/2 expressions associated with their promoter hypermethylations predict adverse prognosis in AML.