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

 Yundeok Kim  ;  Hoi Kyung Jeung  ;  June Won Cheong  ;  Jaewoo Song  ;  Soo Han Bae  ;  Jong In Lee  ;  Yoo Hong Min 
 YONSEI MEDICAL JOURNAL, Vol.61(9) : 762-773, 2020-09 
Journal Title
Issue Date
Aminopyridines / pharmacology* ; Antineoplastic Agents / pharmacology* ; Cell Differentiation / drug effects* ; Drug Resistance, Neoplasm / drug effects* ; Drug Resistance, Neoplasm / genetics ; Enzyme Inhibitors / pharmacology* ; Humans ; Isocitrate Dehydrogenase / antagonists & inhibitors ; Isocitrate Dehydrogenase / genetics* ; Isocitrate Dehydrogenase / metabolism ; Leukemia, Myeloid, Acute / drug therapy* ; Leukemia, Myeloid, Acute / genetics ; Mutation ; Tretinoin / pharmacology* ; Triazines / pharmacology*
Isocitrate dehydrogenase 2-mutant acute myeloid leukemia ; all-trans retinoic acid ; combination treatment ; differentiation ; isocitrate dehydrogenase 2 inhibitor
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.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
Yonsei Authors
Min, Yoo Hong(민유홍) ORCID logo https://orcid.org/0000-0001-8542-9583
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
Song, Jae Woo(송재우) ORCID logo https://orcid.org/0000-0002-1877-5731
Cheong, June-Won(정준원) ORCID logo https://orcid.org/0000-0002-1744-0921
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