Targeting NF-κB in Waldenstrom macroglobulinemia

Xavier Leleu, Jérôme Eeckhoute, Xiaoying Jia, Aldo M. Roccaro, Anne Sophie Moreau, Mena Farag, Antonio Sacco, Hai T. Ngo, Judith Runnels, Molly R. Melhem, Nicolas Burwick, Abdelkareem Azab, Feda Azab, Zachary Hunter, Evdoxia Hatjiharissi, Daniel R. Carrasco, Steven P. Treon, Thomas E. Witzig, Teru Hideshima, Myles BrownKenneth C.Anderson, Irene M. Ghobrial

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79 Scopus citations

Abstract

The nuclear factor-κ-B (NF-κB) pathway has been implicated in tumor B-cell survival, growth, and resistance to therapy. Because tumor cells overcome single-agent antitumor activity, we hypothesized that combination of agents that target differentially NF-κB pathway will induce significant cytotoxicity. Therapeutic agents that target proteasome and Akt pathways should induce significant activity in B-cell malignancies as both pathways impact NF-κB activity. We demonstrated that perifosine and bortezomib both targeted NF-κB through its recruitment to the promoter of its target gene IκB using chromatin immunoprecipitation assay. This combination led to synergistic cytotoxicity in Waldenstrom macroglobulinemia (WM) cells that was mediated through a combined reduction of the PI3K/Akt and ERK signaling pathways, found to be critical for survival of WM cells. Moreover, a combination of these drugs with the CD20 monoclonal antibody rituximab further increased their cytotoxic activity. Thus, effective WM therapy may require combination regimens targeting the NF-κB pathway.

Original languageEnglish (US)
Pages (from-to)5068-5077
Number of pages10
JournalBlood
Volume111
Issue number10
DOIs
StatePublished - May 15 2008

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Leleu, X., Eeckhoute, J., Jia, X., Roccaro, A. M., Moreau, A. S., Farag, M., Sacco, A., Ngo, H. T., Runnels, J., Melhem, M. R., Burwick, N., Azab, A., Azab, F., Hunter, Z., Hatjiharissi, E., Carrasco, D. R., Treon, S. P., Witzig, T. E., Hideshima, T., ... Ghobrial, I. M. (2008). Targeting NF-κB in Waldenstrom macroglobulinemia. Blood, 111(10), 5068-5077. https://doi.org/10.1182/blood-2007-09-115170