Targeting neddylation effectively antagonizes nuclear factor-κB in chronic lymphocytic leukemia B-cells.
Leuk Lymphoma
; 56(5): 1566-9, 2015 May.
Article
em En
| MEDLINE
| ID: mdl-26086969
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.
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MEDLINE
Assunto principal:
Leucemia Linfocítica Crônica de Células B
/
NF-kappa B
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article