Retinoic Acid and Arsenic Trioxide Induce Lasting Differentiation and Demethylation of Target Genes in APL Cells

Overview

Journal Sci Rep

Specialty Science

Date 2019 Jul 3

PMID 31263158

Citations 21

Authors

Thomas T Huynh

Mohammad Sultan

Dejan Vidovic

Cheryl A Dean

Brianne M Cruickshank

Kristen Lee

Chao-Yu Loung

Ryan W Holloway

David W Hoskin

David M Waisman

Ian C G Weaver

Paola Marcato

Affiliations

Soon will be listed here.

Abstract

Acute promyelocytic leukemia (APL) is characterized by arrested differentiation of promyelocytes. Patients treated with all-trans retinoic acid (ATRA) alone experience relapse, while patients treated with ATRA and arsenic trioxide (ATO) are often relapse-free. This suggests sustained changes have been elicited by the combination therapy. To understand the lasting effects of the combination therapy, we compared the effects of ATRA and ATO on NB4 and ATRA-resistant NB4-MR2 APL cells during treatment versus post treatment termination. After treatment termination, NB4 cells treated with ATRA or ATO reverted to non-differentiated cells, while combination-treated cells remained terminally differentiated. This effect was diminished in NB4-MR2 cells. This suggests combination treatment induced more permanent changes. Combination treatment induced higher expression of target genes (e.g., transglutaminase 2 and retinoic acid receptor beta), which in NB4 cells was sustained post treatment termination. To determine whether sustained epigenetic changes were responsible, we quantified the enrichment of histone modifications by chromatin immunoprecipitation, and CpG methylation by bisulfite-pyrosequencing. While ATRA and combination treatment induced similar histone acetylation enrichment, combination treatment induced greater demethylation of target genes, which was sustained. Therefore, sustained demethylation of target genes by ATRA and ATO combination treatment is associated with lasting differentiation and gene expression changes.

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