SCYLD expression leads to CLL in mice and men

Abstract

Abstract A tightly regulated NF-κB pathway is very important for B cell homeostasis. Aberrant activation of NF-κB is involved in the development of chronic lymphocytic leukemia (CLL). The deubiquitinating enzyme CYLD, acts as a negative regulator of NF-κB by removing K63-linked ubiquitin chains from its target proteins. Here, we show that the B cell specific deletion of full-length CYLD and expression of the shorter splice form (sCYLD) lacking the binding sites for TRAF2 and NEMO, leads to the dramatic expansion of CD5 positive B cells, a hallmark of CLL. These cells accumulate in the blood and lymphatic organs with age, and show characteristic up-regulation of typical CLL-markers such as ZAP-70 and Bcl-2. A20, another negative regulator of NF-κB targets some of the same proteins as CYLD, thereby potentially compensating for the lack of FL-CYLD. We crossed sCYLD mice to a B cell specific A20 knockout. In these mice, the CLL phenotype progresses more rapidly probably due to an increase of NF-κB activity, up to the point where 100% of the B cells are CD5+. These cells show oligoclonal expansion, infiltrate the liver and the lungs, and accumulate in all lymphatic organs. Interestingly, we could show that some human CLL patients also express sCYLD, whereas none of the healthy controls do. These findings indicate that sCYLD is a new risk factor for CLL and implies that disrupted alternative splicing of key NF-κB regulators lead to the development of CLL.