title: Targeting neddylation effectively antagonizes nuclear factor-κB in chronic lymphocytic leukemia B-cells.
abstract: Chronic lymphocytic leukemia (CLL) B-cells demonstrate both constitutive and stroma-mediated activation of nuclear factor-κB (NF-κB). NEDD8, a ubiquitin-like protein, regulates activity of Cullin-RING ubiquitin ligases (CRLs) and thus indirectly controls NF-κB activity. Inhibition of CRLs with MLN4924, an investigational agent that targets the NEDD8-activating enzyme, induces accumulation of CRL substrates, including inhibitor of NF-κB (IκB), a negative pathway modulator. We demonstrate that both continuous and pulse treatments with MLN4924 abrogate NF-κB activity in CLL B-cells ex vivo in a CD40L-expressing stromal co-culture system and identify pathways potentially responsible for resistance to MLN4924. To achieve long-lasting therapeutic effects in CLL, combination strategies are likely necessary.
authors.affiliation: Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center , Lebanon, NH , USA.
authors.forename: J Claire
authors.initials: JC
authors.lastname: Godbersen
authors.forename: Cody
authors.initials: C
authors.lastname: Paiva
authors.forename: Olga V
authors.initials: OV
authors.lastname: Danilova
authors.forename: Allison
authors.initials: A
authors.lastname: Berger
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Alexey V
authors.initials: AV
authors.lastname: Danilov
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism*; D000075687:NEDD8 Protein; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D014158:Transcription, Genetic; D014452:Ubiquitins / Q000378:metabolism
chemical_list: D003517:Cyclopentanes; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D016328:NF-kappa B; D011743:Pyrimidines; D014452:Ubiquitins; C539933:pevonedistat
keywords: Chronic lymphocytic leukemia; MLN4924; NF-κB; neddylation