Targeting Microenvironment-Mediated NFκb Activation With MLN4924, An Inhibitor Of The Nedd8-Activating Enzyme, In Chronic Lymphocytic Leukemia B Cells
Claire Godbersen, Alan Eastman, Jennifer R. Brown et al.
Key Points:
B-cell receptor (BCR) and CD40 signaling-> NFκB pathway activity in CLL cells leading to protection from spontaneous apoptosis.
Protective against drug-induced apoptosis.
MLN4924, inhibitor of Nedd8-Activating Enzyme, reduces neddylation of Cullin-RING ubiquitin ligases and accumulation of phospho-IκBa, and leads to modest apoptosis in CLL cells.
Presence of MLN4924 -> decrease in nuclear translocation of the NFκB subunits p65 and p52 in CLL cells leading to de-activation of both canonical and non-canonical pathways.
MLN4924 downregulates cytokine ligands and receptors expressed by the CLL cells.
Pomotes induction of Bim and Noxa in CLL cells which preceded apoptosis.
Implications:
- MLN4924: re-expression of pro-apoptotic BH3-only proteins and interference with chemokine network in CLL cells.
View the original abstract on the ASH website.
