MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) 
inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of 
DNA rereplication, resulting in DNA damage and cell death. However, in 
preclinical models of activated B cell-like (ABC) diffuse large B-cell lymphoma 
(DLBCL), we show that MLN4924 induces an alternative mechanism of action. 
Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of 
pIkappaBalpha, decrease in nuclear p65 content, reduction of nuclear 
factor-kappaB (NF-kappaB) transcriptional activity, and G(1) arrest, ultimately 
resulting in apoptosis induction, events consistent with potent NF-kappaB 
pathway inhibition. Treatment of germinal-center B cell-like (GCB) DLBCL cells 
resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, 
consistent with cells undergoing DNA rereplication. In vivo administration of 
MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE 
pathway biomarkers and resulted in complete tumor growth inhibition. In primary 
human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-kappaB pathway 
inhibition accompanied by tumor regressions. This work describes a novel 
mechanism of targeted NF-kappaB pathway modulation in DLBCL and provides strong 
rationale for clinical development of MLN4924 against NF-kappaB-dependent 
lymphomas.