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자료유형
학술저널
저자정보
김윤덕 (연세대학교) 정회경 (연세대학교) 정준원 (연세대학교) 송재우 (연세대학교) 배수한 (연세대학교) 이종인 (연세대학교) 민유홍 (연세대학교)
저널정보
연세대학교 의과대학 Yonsei Medical Journal Yonsei Medical Journal 제61권 제9호
발행연도
2020.1
수록면
762 - 773 (12page)

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Purpose: Pharmacological inhibition of mutant isocitrate dehydrogenase (IDH) reduces R-2-hydroxyglutarate (2-HG) levels andrestores cellular differentiation in vivo and in vitro. The IDH2 inhibitor enasidenib (AG-221) has been approved by the FDA as afirst-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 themechanisms 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 IDH2mutation 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 differentiationamong IDH2-mutant AML cells and primary AML cells expressing IDH2 mutation. Combined treatment with AG-221 andATRA altered autophagic activity. AG-221 and ATRA treatment-induced differentiation of IDH2-mutant AML cells was associatedwith autophagy induction, without suppressing autophagy flux at maturation and degradation stages. A RAF-1/MEK/ERK pathwaywas founded to be associated with AG-221 and ATRA-induced differentiation in IDH2-mutant AML cells. IDH-associated changesin 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 furtherimprovements or increases in response rates in IDH2-mutant AML patients who do not appear to benefit from treatments withIDH2 inhibitor alone.

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