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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 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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등록된 정보가 없습니다.
참고문헌 (37)
참고문헌 신청
Döhner H / 2017 / Diagnosis and management of AML in adults : 2017 ELN recommendations from an international expert panel / Blood 129:424~447
Estey E / 2006 / Acute myeloid leukaemia / Lancet 368:1894~1907
Walter RB / 2010 / Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia : a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study / J Clin Oncol 28:1766~1771
Juliusson G / 2012 / Acute myeloid leukemia in the real world : why population-based registries are needed / Blood 119:3890~3899
Tocci A / 1996 / Dual action of retinoic acid on human embryonic/fetal hematopoiesis : blockade of primitive progenitor proliferation and shift from multipotent/erythroid/monocytic to granulocytic differentiation program / Blood 88:2878~2888
Estey E / 2006 / Acute myeloid leukaemia / Lancet 368:1894~1907
Walter RB / 2010 / Effect of complete remission and responses less than complete remission on survival in acute myeloid leukemia : a combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study / J Clin Oncol 28:1766~1771
Juliusson G / 2012 / Acute myeloid leukemia in the real world : why population-based registries are needed / Blood 119:3890~3899
Tocci A / 1996 / Dual action of retinoic acid on human embryonic/fetal hematopoiesis : blockade of primitive progenitor proliferation and shift from multipotent/erythroid/monocytic to granulocytic differentiation program / Blood 88:2878~2888
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