Demethylation and Up-Regulation of an Oncogene after Hypomethylating Therapy

摘要

Background:Although hypomethylating agents are currently used to treat patients with cancer,whether they can also reactivate and up-regulate oncogenes is not well elucidated.Methods:We examined the effect of hypomethylating agents on SALL4,a known oncogene that plays an important role in myelodysplastic syndrome and other cancers.Paired bone marrow samples that were obtained from two cohorts of patients with myelodysplastic syndrome before and after treatment with a hypomethylating agent were used to explore the relationships among changes in SALL4 expression,treatment response,and clinical outcome.Leukemic cell lines with low or undetectable SALL4 expression were used to study the relationship between SALL4 methylation and expression.A locus-specific demethylation technology,CRISPR-DNMT1-interacting RNA(CRISPR-DiR),was used to identify the CpG island that is critical for SALL4 expression.