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The lymph node microenvironment promotes B-cell receptor signaling, NF-κB activation, and tumor proliferation in chronic lymphocytic leukemia

Yair Herishanu, Patricia Pérez-Galán, Delong Liu, Angélique Biancotto, Stefania Pittaluga, Berengere Vire, Federica Gibellini, Ndegwa Njuguna, Elinor Lee, Lawrence Stennett, Nalini Raghavachari, Poching Liu, J. Philip McCoy, Mark Raffeld, Maryalice Stetler-Stevenson, Constance Yuan, Richard Sherry, Diane C. Arthur, Irina Maric, Therese White, Gerald E Marti, Peter Munson, Wyndham H Wilson and Adrian Wiestner

Abstract

Chronic lymphocytic leukemia (CLL), an incurable malignancy of mature B-lymphocytes involves blood, bone marrow, and secondary lymphoid organs. A role of the tissue microenvironment in the pathogenesis of CLL is hypothesized based on in vitro observations but its contribution in vivo remain ill-defined. To elucidate effects of tumor host interactions in vivo we purified tumor cells from 24 treatment naïve patients. Samples were obtained concurrently from blood, bone marrow and/or lymph node and analyzed by gene expression profiling. Here, we identify the lymph node as a key site in CLL pathogenesis. CLL cells in the lymph node showed upregulation of gene signatures indicating B-cell receptor (BCR) and NF-κB activation. Consistent with antigen dependent BCR signaling and canonical NF-κB activation, we detected phosphorylation of SYK and IκBα, respectively. Expression of BCR target genes was stronger in clinically more aggressive CLL indicating more effective BCR signaling in this subtype in vivo. Tumor proliferation quantified by expression of E2F and c-MYC target genes and verified by Ki67 staining by flow cytometry was highest in lymph node and correlated with clinical disease progression. These data identify the disruption of tumor microenvironment interactions and inhibition of BCR signaling as promising therapeutic strategies in CLL. This study is registered at http://clinicaltrials.gov as NCT00019370.

  • Submitted May 13, 2010.
  • Accepted September 17, 2010.