RELB-dependency uniquely distinguishes Hodgkin lymphoma from Non-Hodgkin lymphomas

Monday, October 24, 2011 — Poster Session I
Noon – 2:00 p.m.	Natcher Conference Center	NCI	CANCER-20

* FARE Award Winner

Authors

• S Ranuncolo
• G Wright
• W Xiao
• S Pittaluga
• E Jaffe
• B Lewis

Abstract

Despite considerable evidence supporting the role of NFkB in the immune system and lymphomagenesis, it is unclear whether specific REL-dimers control a particular set-of-target-genes. Knock-down of each REL member, by shRNAs, showed a dependency on RELA and REL (canonical NFkB signaling) for all non-Hodgkin Lymphomas (NHL), but only Hodgkin lymphomas (HL) were sensitive to RELB knock-down (alternative arm). Activation of this pathway centers on NIK modulation. The complex TRAF-2/TRAF-3/c-AIP-1/c-AIP-2 that targets NIK for ubiquitin-dependent-degradation is impaired in HL cells allowing NIK stabilization and accumulation. We also found this in the HL patients biopsies analyzed. Furthermore, we found that the non-canonical-NFkB-signaling is kept on by a positive-autoregulatory-loop in HL cells. ChIP-seq data merged with expression data following RELB knock-down uncovered BCL2 and BCL-xL as the key RELB downstream targets. Expression of a BCL2 cDNA rescued HL cells from the shRELB toxicity. Strikingly, the down-regulation of BCL2 and BCL-xl upon RELB depletion allows HL cells to die by autophagy. We found that HL is the only B-cell malignancy that depends on RELB for viability, and thus differentiates HL from NHL. The specificity of the RELB for HL makes RELB and the alternative-NFkB-pathway an attractive therapeutic target.

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