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Methylation‐associated DOK1 and DOK2 down‐regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia
Author(s) -
He PinFang,
Xu ZiJun,
Zhou JingDong,
Li XiXi,
Zhang Wei,
Wu DeHong,
Zhang ZhiHui,
Lian XinYue,
Yao XinYu,
Deng ZhaoQun,
Lin Jiang,
Qian Jun
Publication year - 2018
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.26271
Subject(s) - myeloid leukemia , methylation , cancer research , dna methylation , bisulfite sequencing , medicine , decitabine , leukemia , myeloid , oncology , biology , gene , gene expression , genetics
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.