Kurzfassung

B-lymphocytes participate in immune responses that require their proliferation, differentiation and hypermutation. Many of these processes, particularly hypermutation, may lead to oncogenic mutations. Indeed, numerous types of lymphomas originate from defects during hypermutation occurring in the germinal centers (GCs). Mutations in NFkB signaling molecules and in negative regulators of NFkB, such as CYLD and A20, have been identified in B cell lymphomas. These deubiquitinating (DUB) enzymes...B-lymphocytes participate in immune responses that require their proliferation, differentiation and hypermutation. Many of these processes, particularly hypermutation, may lead to oncogenic mutations. Indeed, numerous types of lymphomas originate from defects during hypermutation occurring in the germinal centers (GCs). Mutations in NFkB signaling molecules and in negative regulators of NFkB, 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 NFkB signaling molecules, including oncogene Bcl-3, thus controlling their activity.
In the first period of funding 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. Interestingly, we could not identify such a population in the control animals nor in mice lacking A20 in B cells. Importantly, we found that doubleBKO mice, that lack both A20 and CYLD in B cells, develop these 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 die 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 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.
In the second funding period we plan to better characterize the CLL-like cells we find in the doubleBKO mice and to establish strategies to treat the disease in these mice. Further, we will analyze CD5+ B cells from CLL patients in order to determine the exact role of CYLD and A20 not only in mice but also in human. Our studies will contribute to the understanding of the mechanisms leading to B cell lymphoma, in particular CLL and diffused large B cell lymphoma (DLBCL) development potentially setting the ground for novel therapeutic interventions.
Furthermore we want to continue our on work how CYLD influences the development of DLBCL and elucidate the molecular mechansims of Bcl-3 action in B cell homeostasis and activation.» weiterlesen» einklappen