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

DC FieldValueLanguage
dc.contributor.author민유홍-
dc.contributor.author배수한-
dc.contributor.author송재우-
dc.contributor.author정준원-
dc.date.accessioned2020-12-01T17:39:18Z-
dc.date.available2020-12-01T17:39:18Z-
dc.date.issued2020-09-
dc.identifier.issn0513-5796-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/180369-
dc.description.abstractPurpose: 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.-
dc.description.statementOfResponsibilityopen-
dc.languageEnglish-
dc.publisherYonsei University-
dc.relation.isPartOfYONSEI MEDICAL JOURNAL-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHAminopyridines / pharmacology*-
dc.subject.MESHAntineoplastic Agents / pharmacology*-
dc.subject.MESHCell Differentiation / drug effects*-
dc.subject.MESHDrug Resistance, Neoplasm / drug effects*-
dc.subject.MESHDrug Resistance, Neoplasm / genetics-
dc.subject.MESHEnzyme Inhibitors / pharmacology*-
dc.subject.MESHHumans-
dc.subject.MESHIsocitrate Dehydrogenase / antagonists & inhibitors-
dc.subject.MESHIsocitrate Dehydrogenase / genetics*-
dc.subject.MESHIsocitrate Dehydrogenase / metabolism-
dc.subject.MESHLeukemia, Myeloid, Acute / drug therapy*-
dc.subject.MESHLeukemia, Myeloid, Acute / genetics-
dc.subject.MESHMutation-
dc.subject.MESHTretinoin / pharmacology*-
dc.subject.MESHTriazines / pharmacology*-
dc.titleAll-Trans Retinoic Acid Synergizes with Enasidenib to Induce Differentiation of IDH2-Mutant Acute Myeloid Leukemia Cells-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentDept. of Internal Medicine (내과학교실)-
dc.contributor.googleauthorYundeok Kim-
dc.contributor.googleauthorHoi Kyung Jeung-
dc.contributor.googleauthorJune Won Cheong-
dc.contributor.googleauthorJaewoo Song-
dc.contributor.googleauthorSoo Han Bae-
dc.contributor.googleauthorJong In Lee-
dc.contributor.googleauthorYoo Hong Min-
dc.identifier.doi10.3349/ymj.2020.61.9.762-
dc.contributor.localIdA01407-
dc.contributor.localIdA01798-
dc.contributor.localIdA01798-
dc.contributor.localIdA02054-
dc.contributor.localIdA02054-
dc.contributor.localIdA03729-
dc.contributor.localIdA03729-
dc.relation.journalcodeJ02813-
dc.identifier.eissn1976-2437-
dc.identifier.pmid32882760-
dc.subject.keywordIsocitrate dehydrogenase 2-mutant acute myeloid leukemia-
dc.subject.keywordall-trans retinoic acid-
dc.subject.keywordcombination treatment-
dc.subject.keyworddifferentiation-
dc.subject.keywordisocitrate dehydrogenase 2 inhibitor-
dc.contributor.alternativeNameMin, Yoo Hong-
dc.contributor.affiliatedAuthor민유홍-
dc.contributor.affiliatedAuthor배수한-
dc.contributor.affiliatedAuthor배수한-
dc.contributor.affiliatedAuthor송재우-
dc.contributor.affiliatedAuthor송재우-
dc.contributor.affiliatedAuthor정준원-
dc.contributor.affiliatedAuthor정준원-
dc.citation.volume61-
dc.citation.number9-
dc.citation.startPage762-
dc.citation.endPage773-
dc.identifier.bibliographicCitationYONSEI MEDICAL JOURNAL, Vol.61(9) : 762-773, 2020-09-
Appears in Collections:
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

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