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Hypermethylation of secreted frizzled-related proteins predicts poor prognosis in non-M3 acute myeloid leukemia

Authors Guo H, Zhang T, Wen X, Zhou JD, Ma J, An C, Zhang W, Xu Z, Lin J, Qian J

Received 8 March 2017

Accepted for publication 31 May 2017

Published 20 July 2017 Volume 2017:10 Pages 3635—3644


Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Ashok Kumar Pandurangan

Peer reviewer comments 2

Editor who approved publication: Dr William Cho

Hong Guo,1,2,* Ting-juan Zhang,2,3,* Xiang-mei Wen,1,2 Jing-dong Zhou,2,3 Ji-chun Ma,1,2 Cui An,4 Wei Zhang,2,3 Zi-jun Xu,1,2 Jiang Lin,1,2 Jun Qian2,3

1Laboratory Center, Affiliated People’s Hospital of Jiangsu University, 2The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City, 3Department of Hematology, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, 4Department of Hematology, People’s Hospital of Yu City, Dezhou, People’s Republic of China

*These authors contributed equally to this work

Objective: Secreted frizzled-related proteins (SFRPs) as Wnt signaling antagonists have been found to be dysregulated by promoter hypermethylation in several cancers including acute myeloid leukemia (AML). This study aimed to investigate the methylated status of SFRPs promoter region and its clinical relevance in Chinese non-M3 AML patients.
Methods: SFRPs methylation in 139 primary non-M3 AML patients was determined using methylation-specific real-time quantitative polymerase chain reaction.
Results: The frequency of aberrant methylation was as follows: 30.2% for SFRP1, 27.3% for SFRP2, 5.0% for SFRP4, and 1.4% for SFRP5. Hypermethylation of at least one SFRP gene occurred in 51.8% (72/139) of non-M3 AML patient samples, which was significantly higher compared to normal control (0/21) (P<0.001). Hypermethylation of SFRP1 was potentially associated with N/K-RAS mutations (P=0.043), and the frequency of SFRPs methylation was higher in patients ≥50 years compared to those <50 years, especially for SFRP2 (P<0.05). Furthermore, both whole cohort and cytogenetically normal (CN) patients with high SFRPs-methylated group showed a shorter overall survival (OS) compared to those with low group (P=0.036 and P=0.035, respectively). Moreover, Cox regression multivariate analysis revealed that SFRPs hypermethylation acts as an independent prognostic biomarker among both whole cohort (hazard ratio =1.804, P=0.026) and CN (hazard ratio =2.477, P=0.023) patients. In leukemic cell line HL60 treated with 5-aza-2'-deoxycytidine, the alteration of SFRP1/2 expression inversely correlated with change in SFRP1/2 methylation (r=-0.975, P=0.005 and r=-0.975, P=0.005, respectively). A tendency of negative correlation was observed between SFRP1 expression and its promoter methylation in AML patients (r=-0.334, P=0.038).
Conclusion: These findings suggested that hypermethylation of SFRP1/2 was a frequent event and silenced SFRP1/2 expression in AML. Moreover, hypermethylation of SFRPs promoter was an adverse risk factor for OS in Chinese non-M3 AML patients.

Keywords: SFRPs, methylation, RQ-MSP, non-M3 AML, prognosis

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