Targeting neddylation effectively antagonizes nuclear factor-κB in chronic lymphocytic leukemia B-cells

Chronic lymphocytic leukemia (CLL) B-cells demonstrate both constitutive and stroma-mediated activation of nuclear factor-kappa B (NF-kappa B). NEDD8, a ubiquitin-like protein, regulates activity of Cullin-RING ubiquitin ligases (CRLs) and thus indirectly controls NF-kappa B activity. Inhibition of CRLs with MLN4924, an investigational agent that targets the NEDD8-activating enzyme, induces accumulation of CRL substrates, including inhibitor of NF-kappa B (I kappa B), a negative pathway modulator. We demonstrate that both continuous and pulse treatments with MLN4924 abrogate NF-kappa B 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.