Inhibition of NEDD8-activating enzyme: A novel approach for the treatment of acute myeloid leukemia

Ronan T Swords, Kevin R. Kelly, Peter G. Smith, James J. Garnsey, Devalingam Mahalingam, Ernest Medina, Kelli Oberheu, Swaminathan Padmanabhan, Michael O'Dwyer, Steffan T. Nawrocki, Francis J. Giles, Jennifer S. Carew

Research output: Contribution to journalArticle

153 Scopus citations

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, DNAdamage, 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-κB activity, DNAdamage, 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.

Original languageEnglish
Pages (from-to)3796-3800
Number of pages5
JournalBlood
Volume115
Issue number18
DOIs
StatePublished - May 6 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

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. https://doi.org/10.1182/blood-2009-11-254862