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

Clin Transl Sci. 2021 Jan;14(1):137-142. doi: 10.1111/cts.12861. Epub 2020 Sep 9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Azacitidine / pharmacology
  • Azacitidine / therapeutic use
  • Cell Line, Tumor
  • Child
  • Clinical Trials, Phase III as Topic
  • Cytarabine / pharmacology*
  • Cytarabine / therapeutic use
  • DNA Methylation / drug effects
  • DNA Methylation / genetics
  • Datasets as Topic
  • Decitabine / pharmacology
  • Decitabine / therapeutic use
  • Drug Resistance, Neoplasm / genetics*
  • Epigenetic Repression / drug effects
  • Epigenetic Repression / genetics*
  • Female
  • Gene Expression Regulation, Leukemic / drug effects
  • HEK293 Cells
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / mortality
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Organic Cation Transport Proteins / genetics*
  • Organic Cation Transport Proteins / metabolism
  • Progression-Free Survival
  • Randomized Controlled Trials as Topic
  • Symporters / genetics*
  • Symporters / metabolism
  • Young Adult

Substances

  • Organic Cation Transport Proteins
  • SLC22A4 protein, human
  • Symporters
  • Cytarabine
  • Decitabine
  • Azacitidine