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 language | English (US) |
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Pages (from-to) | 1566-1569 |
Number of pages | 4 |
Journal | Leukemia and Lymphoma |
Volume | 56 |
Issue number | 5 |
DOIs | |
State | Published - May 1 2015 |
Keywords
- Chronic lymphocytic leukemia
- MLN4924
- NF-κB
- Neddylation
ASJC Scopus subject areas
- Hematology
- Oncology
- Cancer Research