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To further understand the mechanistic basis of interindividual variability in the functional expression of OCTN1 in AML, we hypothesized a mechanistic connection to DNA methylation\u2010based epigenetic repression of <jats:italic>SLC22A4<\/jats:italic>. We found increased basal <jats:italic>SLC22A4<\/jats:italic> methylation was associated with decreased Ara\u2010C uptake in AML cell lines. Pre\u2010treatment with hypomethylating agents, 5\u2010azacytidine, or decitabine, restored <jats:italic>SLC22A4<\/jats:italic> mRNA expression, increased cellular uptake of Ara\u2010C, and was associated with increased cellular sensitivity to Ara\u2010C compared with vehicle\u2010treated cells. Additionally, lower <jats:italic>SLC22A4<\/jats:italic> methylation status was associated with distinct clinical advantages in both adult and pediatric patients with AML. These findings suggest a regulatory mechanism is involved in the interindividual variability in response to Ara\u2010C, and provides a basis for the integration of hypomethylating agents into Ara\u2010C\u2010based treatment regimens.<\/jats:p>","DOI":"10.1111\/cts.12861","type":"journal-article","created":{"date-parts":[[2020,9,18]],"date-time":"2020-09-18T07:15:13Z","timestamp":1600413313000},"page":"137-142","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["DNA Methylation\u2010Based Epigenetic Repression of <i>SLC22A4<\/i> Promotes Resistance to Cytarabine in Acute Myeloid Leukemia"],"prefix":"10.1111","volume":"14","author":[{"given":"Daelynn R.","family":"Buelow","sequence":"first","affiliation":[{"name":"Division of Pharmaceutics and Pharmacology College of Pharmacy and Comprehensive Cancer Center The Ohio State University  Columbus Ohio 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