Combination of azacitidine and enasidenib enhances leukemic cell differentiation and cooperatively hypomethylates DNA.

Autor: MacBeth KJ; Bristol Myers Squibb, Princeton, NJ. Electronic address: kjmacbeth@gmail.com., Chopra VS; Bristol Myers Squibb, Princeton, NJ., Tang L; Bristol Myers Squibb, Princeton, NJ., Zheng B; Bristol Myers Squibb, Princeton, NJ., Avanzino B; Bristol Myers Squibb, Princeton, NJ., See WL; Bristol Myers Squibb, Princeton, NJ., Schwickart M; Bristol Myers Squibb, Princeton, NJ., Figueroa ME; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL., Quek L; MRC Molecular Hematology Unit, WIMM University of Oxford, Oxford, UK., DiMartino JF; Bristol Myers Squibb, Princeton, NJ.
Jazyk: angličtina
Zdroj: Experimental hematology [Exp Hematol] 2021 Jun; Vol. 98, pp. 47-52.e6. Date of Electronic Publication: 2021 Mar 29.
DOI: 10.1016/j.exphem.2021.03.003
Abstrakt: Azacitidine and enasidenib are two therapies available for treatment of acute myelogenous leukemia (AML), and the mechanisms of action of these drugs involve alteration of aberrant DNA methylation. We hypothesized that a combination of these agents could have interactive effects on DNA methylation and enhance differentiation in mIDH2 cells. Combination treatment enhanced cellular differentiation in TF-1 cells overexpressing IDJ2R140Q through increased hemoglobinization and increased hemoglobin γ RNA expression compared with the effects of single agents. Furthermore, in primary AML samples (IDH2R140Q or R172K), combination treatment reduced CD34+ cells and increased CD15+ cells to a greater extent than attained with single agents. To explore the mechanism of enhanced differentiation with combination treatment, the TF-1 epigenome was analyzed by profiling 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) DNA methylation changes. Enasidenib treatment alone increased 5hmC, consistent with reactivation of ten-eleven-translocation (TET) enzyme activity. Compared with treatment with azacitidine alone, combination treatment reduced 5mC levels at greater numbers of sites and these loci were significantly enriched in regions with increased 5hMC (25.8% vs. 7.4%). Results are consistent with a model in which enasidenib-mediated reactivation of ten-eleven-translocation enzymes cooperates with azacitidine-mediated inhibition of DNA methyltransferase enzymes, leading to greater reductions in DNA methylation and enhanced erythroid differentiation.
Competing Interests: Conflict of interest disclosure KJM, VSC, LT, BZ, BA, WLS, MS, and JFD are employees of and/or hold stock in Bristol Myers Squibb (formerly Celgene Corp.). MEF declares no conflicts of interest. LQ has received research funding from Celgene.
(Copyright © 2021 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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