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

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


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
Pages (from-to)5068-5077
Number of pages10
Issue number10
StatePublished - May 15 2008


Dive into the research topics of 'Targeting NF-κB in Waldenstrom macroglobulinemia'. Together they form a unique fingerprint.

Cite this