title: The NEDD8-activating enzyme inhibitor MLN4924 induces G2 arrest and apoptosis in T-cell acute lymphoblastic leukemia.
abstract: The first-in-class compound MLN4924 is a small molecule inhibitor that selectively inactivates NEDD8-activating enzyme (NAE). The anticancer effects of MLN4924 have been attributed to impaired neddylation of Cullin proteins. Here, we show that treatment of T-cell acute lymphoblastic leukemia (T-ALL) cells with MLN4924 potently suppressed the neddylation of Cullins and the oncogenic growth of T-ALL cells in-vitro. Moreover, MLN4924 induced disease regression in an in vivo xenograft model. MLN4924 also induced cell cycle arrest at G2 phase and apoptosis in T-ALL cells. However, inhibition of the neddylation of Cullins alone could not explain the effects of MLN4924 in T-ALL cells. Gene expression profiling indicated ribosome function, steroid biosynthesis, and hematopoietic cell lineage pathways were affected by MLN4924 treatment. MLN4924 also induced nucleolar disruption, suggesting nucleolar stress signaling might contribute to the anticancer effects of MLN4924 in T-ALL cells. In addition, MLN4924 treatment reduced 14-3-3ξ\δ protein levels in T-ALL cells. Thus, MLN4924 may inhibit T-ALL cell proliferation via several pathways.
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Kun
authors.initials: K
authors.lastname: Han
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Huanling
authors.initials: H
authors.lastname: Cao
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Guihua
authors.initials: G
authors.lastname: Qiu
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.affiliation: Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing 100850, P. R. China.
authors.forename: Jiyan
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D003517:Cyclopentanes / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000075687:NEDD8 Protein / Q000378:metabolism*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; C539933:pevonedistat
keywords: G2 arrest; MLN4924; T-ALL; apoptosis; neddylation