All-Trans Retinoic Acid Synergizes with Enasidenib to Induce Differentiation of IDH2-Mutant Acute Myeloid Leukemia Cells
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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.
Abstract
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.
참고문헌 (37)
- Döhner H, "Diagnosis and management of AML in adults : 2017 ELN recommendations from an international expert panel", Blood, 129, pp.424~447 (2017)
- Estey E, "Acute myeloid leukaemia", Lancet, 368, pp.1894~1907 (2006)
- Walter RB, "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, pp.1766~1771 (2010)
- Juliusson G, "Acute myeloid leukemia in the real world : why population-based registries are needed", Blood, 119, pp.3890~3899 (2012)
- Tocci A, "Dual action of retinoic acid on human embryonic", fetal hematopoiesis : blockade of primitive progenitor proliferation and shift from multipotent, monocytic to granulocytic differentiation program, pp.Blood, 1996[DOI]
- Fenaux P, "All-trans retinoic acid and chemotherapy in the treatment of acute promyelocytic leukemia", Semin Hematol, 38, pp.13~25 (2001)
- Fenaux P, "Long-term follow-up confirms the benefit of all-trans retinoic acid in acute promyelocytic leukemia. European APL group", Leukemia, 14, pp.1371~1377 (2000)
- Cancer Genome Atlas Research Network, "Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia", N Engl J Med, 368, pp.2059~2074 (2013)
- Gross S, "Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations", J Exp Med, 207, pp.339~344 (2010)
- Janin M, "Serum 2-hydroxyglutarate production in IDH1-and IDH2-mutated de novo acute myeloid leukemia : a study by the Acute Leukemia French Association group", J Clin Oncol, 32, pp.297~305 (2014)
- Parsons DW, "An integrated genomic analysis of human glioblastoma multiforme", Science, 321, pp.1807~1812 (2008)
- Pansuriya TC, "Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome", Nat Genet, 43, pp.1256~1261 (2011)
- Borger DR, "Frequent mutation of isocitrate dehydrogenase(IDH)1 and IDH2 in cholangiocarcinoma identified through broad-based tumor genotyping", Oncologist, 17, pp.72~79 (2012)
- Figueroa ME, "Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation", Cancer Cell, 18, pp.553~567 (2010)
- Fathi AT, "Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response", Blood, 120, pp.4649~4652 (2012)
- Lu C, "IDH mutation impairs histone demethylation and results in a block to cell differentiation", Nature, 483, pp.474~478 (2012)
- Popovici-Muller J, "Discovery of the first potent inhibitors of mutant IDH1 that lower tumor 2-HG in vivo", ACS Med Chem Lett, 3, pp.850~855 (2012)
- Stein EM, "Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia", Blood, 130, pp.722~731 (2017)
- Shih AH, "Combination targeted therapy to disrupt aberrant oncogenic signaling and reverse epigenetic dysfunction in IDH2-and TET2-mutant acute myeloid leukemia", Cancer Discov, 7, pp.494~505 (2017)
- Boutzen H, "Isocitrate dehydrogenase 1 mutations prime the all-trans retinoic acid myeloid differentiation pathway in acute myeloid leukemia", J Exp Med, 213, pp.483~497 (2016)
- Kim YR, "Myeloperoxidase expression as a potential determinant of parthenolide-induced apoptosis in leukemia bulk and leukemia stem cells", J Pharmacol Exp Ther, 335, pp.389~400 (2010)
- Wang F, "Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation", Science, 340, pp.622~626 (2013)
- Mizushima N, "Methods in mammalian autophagy research", Cell, 140, pp.313~326 (2010)
- Kihara A, "Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network", EMBO Rep, 2, pp.330~335 (2001)
- Mauvezin C, "Bafilomycin A1 disrupts autophagic flux by inhibiting both V-ATPase-dependent acidification and Ca-P60A", SERCA-dependent autophagosome-lysosome fusion, 2015, pp.11, 1437~1438
- Battle TE, "Retinoic acid-induced blr1 expression requires RARalpha, RXR, and MAPK activation and uses ERK2 but not JNK", SAPK to accelerate cell differentiation, 2001, pp.80, 59~67
- Piskunov A, "A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK", Oncogene, 31, pp.3333~3345 (2012)
- Amatangelo MD, "Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response", Blood, 130, pp.732~741 (2017)
- Yen K, "AG-221, a first-in-class therapy targeting acute myeloid leukemia harboring oncogenic IDH2 mutations", Cancer Discov, 7, pp.478~493 (2017)
- Stein EM, "Emerging therapeutic drugs for AML", Blood, 127, pp.71~78 (2016)
- Guan JL, "Autophagy in stem cells", Autophagy, 9, pp.830~849 (2013)
- Mizushima N, "Autophagy in mammalian development and differentiation", Nat Cell Biol, 12, pp.823~830 (2010)
- Conway KL, "ATG5 regulates plasma cell differentiation", Autophagy, 9, pp.528~537 (2013)
- Orfali N, "Induction of autophagy is a key component of alltrans-retinoic acid-induced differentiation in leukemia cells and a potential target for pharmacologic modulation", Exp Hematol, 43, pp.781~793 (2015)
- Weng XQ, "RAF-1", MEK, EBPβ, C, pp.EBPβ and PU. 1, Leuk Res[DOI]
- Hong HY, "Retinoic acid causes MEK-dependent RAF phosphorylation through RARalpha plus RXR activation in HL-60 cells", Differentiation, 68, pp.55~66 (2001)
- Xu W, "Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutaratedependent dioxygenases", Cancer Cell, 19, pp.17~30 (2011)