title: MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors.
abstract: MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, MN, USA.
authors.forename: K L B
authors.initials: KL
authors.lastname: Knorr
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: P A
authors.initials: PA
authors.lastname: Schneider
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, MN, USA.|Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: X W
authors.initials: XW
authors.lastname: Meng
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, MN, USA.|Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: H
authors.initials: H
authors.lastname: Dai
authors.affiliation: Division of Hematological Malignancies, Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, MD, USA.
authors.forename: B D
authors.initials: BD
authors.lastname: Smith
authors.affiliation: Division of Hematological Malignancies, Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, MD, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Hess
authors.affiliation: Division of Hematological Malignancies, Sidney Kimmel Cancer Center, Johns Hopkins, Baltimore, MD, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Karp
authors.affiliation: Department of Molecular Pharmacology and Experimental Therapeutics, Rochester, MN, USA.|Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: S H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology*; D004357:Drug Synergism; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003517:Cyclopentanes; C579095:MCL1 protein, human; C489427:MYC protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013449:Sulfonamides; C579720:venetoclax; C539933:pevonedistat