All-Trans Retinoic Acid Synergizes with Enasidenib to Induce Differentiation of IDH2-Mutant Acute Myeloid Leukemia Cells

Overview

Journal Yonsei Med J

Specialty General Medicine

Date 2020 Sep 4

PMID 32882760

Citations 7

Authors

Yundeok Kim

Hoi Kyung Jeung

June Won Cheong

Jaewoo Song

Soo Han Bae

Jong In Lee

Yoo Hong Min

Affiliations

Soon will be listed here.

Abstract

Purpose: Pharmacological inhibition of mutant isocitrate dehydrogenase (IDH) reduces R-2-hydroxyglutarate (2-HG) levels and restores cellular differentiation in vivo and in vitro. The IDH2 inhibitor enasidenib (AG-221) has been approved by the FDA as a first-in-class inhibitor for the treatment of relapsed or refractory (R/R) IDH2-mutant acute myeloid leukemia (AML). In this study, the effects of a combination of all-trans retinoic acid (ATRA) and AG-221 on AML cell differentiation was explored, along with the mechanisms employed by IDH2-mutant cells in AML.

Materials And Methods: We treated the human AML cell line, IDH2-mutant-TF-1, and primary human AML cells carrying IDH2 mutation with 30 μM AG-221 and 100 nM ATRA, alone or in combination.

Results: Combined treatment with AG-221 and ATRA inhibited 2-HG production and resulted in synergistic effects on differentiation among IDH2-mutant AML cells and primary AML cells expressing IDH2 mutation. Combined treatment with AG-221 and ATRA altered autophagic activity. AG-221 and ATRA treatment-induced differentiation of IDH2-mutant AML cells was associated with autophagy induction, without suppressing autophagy flux at maturation and degradation stages. A RAF-1/MEK/ERK pathway was founded to be associated with AG-221 and ATRA-induced differentiation in IDH2-mutant AML cells. IDH-associated changes in histone methylation markers decreased after AG-221 and ATRA combination treatment.

Conclusion: Our preliminary evidence indicates that the addition of ATRA to treatments with IDH2 inhibitor may lead to further improvements or increases in response rates in IDH2-mutant AML patients who do not appear to benefit from treatments with IDH2 inhibitor alone.

Citing Articles

Clinical Implications of Isocitrate Dehydrogenase Mutations and Targeted Treatment of Acute Myeloid Leukemia with Mutant Isocitrate Dehydrogenase Inhibitors-Recent Advances, Challenges and Future Prospects.

Kowalczyk A, Zarychta J, Lejman M, Latoch E, Zawitkowska J Int J Mol Sci. 2024; 25(14).

PMID: 39063158 PMC: 11276768. DOI: 10.3390/ijms25147916.

All-trans retinoic acid in hematologic disorders: not just acute promyelocytic leukemia.

Chen Y, Tong X, Lu R, Zhang Z, Ma T Front Pharmacol. 2024; 15:1404092.

PMID: 39027338 PMC: 11254857. DOI: 10.3389/fphar.2024.1404092.

Isocitrate dehydrogenase 2 inhibitor enasidenib synergizes daunorubicin cytotoxicity by targeting aldo-keto reductase 1C3 and ATP-binding cassette transporters.

Morell A, Budagaga Y, Vagiannis D, Zhang Y, Lastovickova L, Novotna E Arch Toxicol. 2022; 96(12):3265-3277.

PMID: 35972551 DOI: 10.1007/s00204-022-03359-2.

IDH2: A novel biomarker for environmental exposure in blood circulatory system disorders.

Gong Y, Wei S, Wei Y, Chen Y, Cui J, Yu Y Oncol Lett. 2022; 24(2):278.

PMID: 35814829 PMC: 9260733. DOI: 10.3892/ol.2022.13398.

2-Hydroxyglutarate in Acute Myeloid Leukemia: A Journey from Pathogenesis to Therapies.

Raimondi V, Ciotti G, Gottardi M, Ciccarese F Biomedicines. 2022; 10(6).

PMID: 35740380 PMC: 9220225. DOI: 10.3390/biomedicines10061359.

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