All-Trans Retinoic Acid Synergizes with Enasidenib to Induce Differentiation of IDH2-Mutant Acute Myeloid Leukemia Cells
10.3349/ymj.2020.61.9.762
- Author:
Yundeok KIM
1
;
Hoi-Kyung JEUNG
;
June-Won CHEONG
;
Jaewoo SONG
;
Soo Han BAE
;
Jong In LEE
;
Yoo Hong MIN
Author Information
1. Department of Internal Medicine, Yonsei Wonju College of Medicine, Wonju
- Publication Type:Original Article
- From:Yonsei Medical Journal
2020;61(9):762-773
- CountryRepublic of Korea
-
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.
