Inhibition of nedd8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia
View/ Open
Full Text
Date
2010-03-04Author
Swords, R. T.
Kelly, K. R.
Smith, P. G.
Garnsey, J. J.
Mahalingam, D.
Medina, E.
Oberheu, K.
Padmanabhan, S.
O'Dwyer, M.
Nawrocki, S. T.
Giles, F. J.
Carew, J. S.
Metadata
Show full item recordUsage
This item's downloads: 0 (view details)
Cited 182 times in Scopus (view citations)
Recommended Citation
Swords, R. T. Kelly, K. R.; Smith, P. G.; Garnsey, J. J.; Mahalingam, D.; Medina, E.; Oberheu, K.; Padmanabhan, S.; O'Dwyer, M.; Nawrocki, S. T.; Giles, F. J.; Carew, J. S. (2010). Inhibition of nedd8-activating enzyme: a novel approach for the treatment of acute myeloid leukemia. Blood 115 (18), 3796-3800
Published Version
Abstract
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)