Abstract
Mutations in NFκB signaling molecules and in negative regulators of NFκB, such as CYLD and A20, have been identified in B cell lymphomas. These deubiquitinating (DUB) enzymes remove activating lysine-63 linked ubiquitin chains from numerous NFκB signaling molecules, including oncogene Bcl-3, thus controlling their activity. We found that mice lacking CYLD specifically in B cells develop with age a marked population of CD5+ B cells in the blood and the body, a population that resembles cells found in CLL patients. Importantly, we found that doubleBKO mice, that lack both A20 and CYLD in B cells, develop CD5+ B cells in an enhanced fashion, already at two months of age, with more than 95% of all B cells expressing CD5 before one year of age. Apart of CD5 expression, these B cells also increasingly express CLL markers, such as ZAP70 and Bcl-2. Starting with 14 month of age, these mouse mutants start to die most probably from CLL pathology. Thus, we could assign a separate, yet essential role for each of these two DUB enzymes in the control of B cell function, and have shown that loss of both together resulted in the initiation of a previously not identified chain of events probably leading to lymphoma/leukemia. In addition, we were able to identify a splice variant of CYLD that we previously found in mice, also in human CLL patients, thus indicating that this molecule, we termed sCYLD, may have a tumor-associated role not only in mice but also in human.
