Abstract
Sprouty-related, EVH1 domain-containing protein 1 (SPRED1) has been identified as a novel tumor suppressor gene in acute myeloid leukemia (AML). Previous studies showed that SPRED1 methylation levels were significantly increased in AML patients, making it an interesting candidate for further investigations. To confirm the association of SPRED1 methylation, clinical parameters, and known molecular prognosticators and to identify the impact of methylation level on treatment outcome, we conducted this study in a larger cohort of 75 AML patients. Significantly increased methylation levels of SPRED1 were detected at four of ten CpG units by quantitative high-resolution mass spectrometry-based approach (MassARRAY) in AML patients. Whereas overall survival (OS) and relapse-free survival (RFS) showed no statistical difference between hypermethylation and hypomethylation subgroups, the relationship between methylation level and treatment response was indicated in paired samples from pre- and post-induction. To determine the possible mechanism of SPRED1 methylation in AML, we performed in vitro experiments using THP-1 cells, as the latter showed the highest methylation level (determined by utilizing bisulfite modification) among the three AML cell lines we tested. When treated with 5-AZA and lentivirus transfection, upregulated SPRED1 expression, decreased cell proliferation, increased cell differentiation and apoptosis, and inactivated phosphorylated extracellular signal-regulated kinase (p-ERK) were detected in THP-1 cells. These results show that demethylation of SPRED1 can inhibit the proliferation of AML cells and promote their differentiation and apoptosis, possibly by the ERK pathway. The hypermethylation of SPRED1 is a potential therapeutic target for AML.
Highlights
Epigenetic modifications, such as abnormal DNA methylation, are believed to play an important role in the occurrence and development of acute myeloid leukemia (AML) [1–3]
A majority of studies have shown that the abnormal DNA methylations of tumor suppressor genes (TSGs) and protooncogenes serve as a prognostic marker of AML [4, 5]
Thanks to recent technological advancement in the field of genome research, studying genomic changes and epigenetic modifications in AML cell lines, such as abnormal DNA methylation, has gained more and more interest [19–21], while using the demethylating agents (HMAs) is definitely effective, especially for patients who are implicated in abnormalities of epigenetic regulation [22, 23]
Summary
Epigenetic modifications, such as abnormal DNA methylation, are believed to play an important role in the occurrence and development of acute myeloid leukemia (AML) [1–3]. A majority of studies have shown that the abnormal DNA methylations of tumor suppressor genes (TSGs) and protooncogenes serve as a prognostic marker of AML [4, 5]. Hypermethylation could serve as a therapeutic target, which frequently occurs in some subtypes of AML, such as in the elderly or in those with myelodysplastic-related or AML with t(8;21) [6, 7]. As an alternative or a complementary choice with traditional chemotherapy, demethylating agents supply an opportunity for longer survival in some specific types of AML [8, 9]. One of the main reasons is that little is known about the targets of demethylating agents themselves, and the specific genes that are hypermethylated drive the leukemogenesis
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