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

• Published in: Journal of cellular physiology Vol. 233; no. 9; pp. 6604 - 6614
• Main Authors: He, Pin‐Fang, Xu, Zi‐Jun, Zhou, Jing‐Dong, Li, Xi‐Xi, Zhang, Wei, Wu, De‐Hong, Zhang, Zhi‐Hui, Lian, Xin‐Yue, Yao, Xin‐Yu, Deng, Zhao‐Qun, Lin, Jiang, Qian, Jun
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.09.2018
• Subjects: Acute myeloid leukemia; Biomarkers; Bisulfite; Cell survival; Demethylation; DOK1; Dok1 protein; DOK2; expression; Leukemia; Medical prognosis; Methylation; Myeloid leukemia; Patients; Prognosis; Protein-tyrosine kinase; Survival; Tyrosine; DOK1; DOK2; expression; acute myeloid leukemia; methylation
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.26271

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. Our study found that DOK1 and DOK2 expressions were significantly down‐regulated in AML patients, and decreased DOK1/2 expressions associated with their promoter hypermethylations predict adverse prognosis in AML.