Targeting neddylation effectively antagonizes nuclear factor-κB in chronic lymphocytic leukemia B-cells

J. Claire Godbersen, Cody Paiva, Olga V. Danilova, Allison Berger, Jennifer R. Brown, Alexey V. Danilov

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

Chronic lymphocytic leukemia (CLL) B-cells demonstrate both constitutive and stroma-mediated activation of nuclear factor-κB (NF-κB). NEDD8, a ubiquitin-like protein, regulates activity of Cullin-RING ubiquitin ligases (CRLs) and thus indirectly controls NF-κB activity. Inhibition of CRLs with MLN4924, an investigational agent that targets the NEDD8-activating enzyme, induces accumulation of CRL substrates, including inhibitor of NF-κB (IκB), a negative pathway modulator. We demonstrate that both continuous and pulse treatments with MLN4924 abrogate NF-κB activity in CLL B-cells ex vivo in a CD40L-expressing stromal co-culture system and identify pathways potentially responsible for resistance to MLN4924. To achieve long-lasting therapeutic effects in CLL, combination strategies are likely necessary.

Original languageEnglish (US)
Pages (from-to)1566-1569
Number of pages4
JournalLeukemia and Lymphoma
Volume56
Issue number5
DOIs
StatePublished - May 1 2015

Keywords

  • Chronic lymphocytic leukemia
  • MLN4924
  • NF-κB
  • Neddylation

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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