Constitutive NF-κB maintains high expression of a characteristic gene network, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells

Abstract

AbstractConstitutively activated nuclear factor (NF)-κB is observed in a variety of neoplastic diseases and is a hallmark of the malignant Hodgkin and Reed-Sternberg cells (H/RS) in Hodgkin lymphoma. Given the distinctive role of constitutive NF-κB for H/RS cell viability, NF-κB–dependent target genes were searched for by using adenoviral expression of the super-repressor IκBΔN. A surprisingly small but characteristic set of genes, including the cell-cycle regulatory protein cyclin D2, the antiapoptotic proteins Bfl-1/A1, c-IAP2, TRAF1, and Bcl-xL, and the cell surface receptors CD86 and CD40 were identified. Thus, constitutive NF-κB activity maintains expression of a network of genes, which are known for frequent, marker-like expression in primary or cultured H/RS cells. Intriguingly, CD40, which is able to activate CD86 or Bcl-xL via NF-κB, is itself transcriptionally regulated by NF-κB through a promoter proximal binding site. NF-κB inhibition resulted in massive spontaneous and p53-independent apoptosis, which could be rescued by ectopic expression of Bcl-xL, underscoring its dominant role in survival of H/RS cells. Hence, NF-κB controls a signaling network in H/RS cells, which promotes tumor cell growth and confers resistance to apoptosis.