Peer-Reviewed Journal Details
Mandatory Fields
Swords, RT,Kelly, KR,Smith, PG,Garnsey, JJ,Mahalingam, D,Medina, E,Oberheu, K,Padmanabhan, S,O'Dwyer, M,Nawrocki, ST,Giles, FJ,Carew, JS
2010
May
Blood
Inhibition of NEDD8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia
Published
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Optional Fields
THERAPEUTIC APPROACH CELLS CANCER UBIQUITINATION RESISTANCE PATHWAY
115
3796
3800
NEDD8 activating enzyme (NAE) has been identified as an essential regulator of the NEDD8 conjugation pathway, which controls the degradation of many proteins with important roles in cell-cycle progression, DNA damage, and stress responses. Here we report that MLN4924, a novel inhibitor of NAE, has potent activity in acute myeloid leukemia (AML) models. MLN4924 induced cell death in AML cell lines and primary patient specimens independent of Fms-like tyrosine kinase 3 expression and stromal-mediated survival signaling and led to the stabilization of key NAE targets, inhibition of nuclear factor-kappa B activity, DNA damage, and reactive oxygen species generation. Disruption of cellular redox status was shown to be a key event in MLN4924-induced apoptosis. Administration of MLN4924 to mice bearing AML xenografts led to stable disease regression and inhibition of NEDDy-lated cullins. Our findings indicate that MLN4924 is a highly promising novel agent that has advanced into clinical trials for the treatment of AML. (Blood. 2010; 115(18):3796-3800)
DOI 10.1182/blood-2009-11-254862
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