Constitutive NF-kappa B maintains high expression of a characteristic genenetwork, including CD40, CD86, and a set of antiapoptotic genes in Hodgkin/Reed-Sternberg cells

Constitutively activated nuclear factor (NF)-kappaB is observed in a variet y of neoplastic diseases and is a hallmark of the malignant Hodgkin and Ree d-Sternberg cells (H/RS) in Hodgkin lymphoma. Given the distinctive role of constitutive NF-kappaB for H/RS cell viability, NF-kappaB-dependent target genes were searched for by using adenoviral expression of the super-repres sor I kappaB DeltaN. A surprisingly small but characteristic set of genes, including the cell-cycle regulatory protein cyclin D2, the antiapoptotic pr oteins Bfl-1/A1, c-IAP2, TRAF1, and Bcl-x(L), and the cell surface receptor s CD86 and CD40 were identified. Thus, constitutive NF-kappaB activity main tains expression of a network of genes, which are known for frequent, marke r-like expression in primary or cultured H/RS cells, intriguingly, CD40, wh ich is able to activate CD86 or Bcl-x(L) via NF-kappaB, is itself transcrip tionally regulated by NF-kappaB through a promoter proximal binding site. N F-kappaB inhibition resulted in massive spontaneous and p53-independent apo ptosis, which could be rescued by ectopic expression of Bcl-x(L), underscor ing its dominant role in survival of H/RS cells. Hence, NF-kappaB controls a signaling network in H/RS cells, which promotes tumor cell growth and con fers resistance to apoptosis. (Blood, 2001;97: 2798-2807) (C) 2001 by The A merican Society of Hematology.