DNA Methylation‐Based Epigenetic Repression of SLC22A4 Promotes Resistance to Cytarabine in Acute Myeloid Leukemia

Reduced expression of the uptake transporter, OCTN1 (SLC22A4), has been reported as a strong predictor of poor event‐free and overall survival in multiple cohorts of patients with acute myeloid leukemia (AML) receiving the cytidine nucleoside analog, cytarabine (Ara‐C). To further understand the mec...

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Bibliographic Details
Published in:	Clinical and translational science Vol. 14; no. 1; pp. 137 - 142
Main Authors:	Buelow, Daelynn R., Anderson, Jason T., Pounds, Stanley B., Shi, Lei, Lamba, Jatinder K., Hu, Shuiying, Gibson, Alice A., Goodwin, Emily A., Sparreboom, Alex, Baker, Sharyn D.
Format:	Journal Article
Language:	English
Published:	United States John Wiley & Sons, Inc 01-01-2021 John Wiley and Sons Inc Wiley
Subjects:	5-aza-2'-deoxycytidine Acute myeloid leukemia Adolescent Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Azacitidine - pharmacology Azacitidine - therapeutic use Azacytidine Brief Report Cancer therapies Cell Line, Tumor Child Clinical trials Clinical Trials, Phase III as Topic Cytarabine Cytarabine - pharmacology Cytarabine - therapeutic use Cytomegalovirus Cytotoxicity Datasets as Topic Decitabine - pharmacology Decitabine - therapeutic use Deoxyribonucleic acid DNA DNA methylation DNA Methylation - drug effects DNA Methylation - genetics Drug Resistance, Neoplasm - genetics Epigenetic Repression - drug effects Epigenetic Repression - genetics Epigenetics Female Gene expression Gene Expression Regulation, Leukemic - drug effects Genomes HEK293 Cells Humans Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - mortality Leukemia, Myeloid, Acute - pathology Male Myeloid leukemia Nucleoside analogs Organic Cation Transport Proteins - genetics Organic Cation Transport Proteins - metabolism Patients Pediatrics Polymerase chain reaction Progression-Free Survival Randomized Controlled Trials as Topic Symporters - genetics Symporters - metabolism Young Adult
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Summary:	Reduced expression of the uptake transporter, OCTN1 (SLC22A4), has been reported as a strong predictor of poor event‐free and overall survival in multiple cohorts of patients with acute myeloid leukemia (AML) receiving the cytidine nucleoside analog, cytarabine (Ara‐C). 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‐based epigenetic repression of SLC22A4. We found increased basal SLC22A4 methylation was associated with decreased Ara‐C uptake in AML cell lines. Pre‐treatment with hypomethylating agents, 5‐azacytidine, or decitabine, restored SLC22A4 mRNA expression, increased cellular uptake of Ara‐C, and was associated with increased cellular sensitivity to Ara‐C compared with vehicle‐treated cells. Additionally, lower SLC22A4 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‐C, and provides a basis for the integration of hypomethylating agents into Ara‐C‐based treatment regimens.
Bibliography:	† These authors contributed equally to this work. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1752-8054 1752-8062
DOI:	10.1111/cts.12861