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The role of the deubiquitinating enzymes Cyld and A20 in B cell lymphomagenesis

Subject Area Cell Biology
African, American and Oceania Studies
Term from 2010 to 2017
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 165257285
 
Final Report Year 2017

Final Report Abstract

In this grand application we investigated how enforced NF-κB activation driven by B-cell specific deletion of the deubiquitinating enzymes, CYLD and A20, affect B-cell lymphomagenesis. It is known that a tightly regulated NF-κB pathway is crucial for B- cell development and homeostasis. Aberrant activation of this pathway has been shown to be involved in chronic lymphocytic leukemia (B-CLL), the most common leukemia in the Western world. CLL is characterized by the accumulation of small CD5+ B lymphocytes with a mature phenotype. Different signaling pathways, such as the nuclear factor kappa B (NF-κB), show constitutive activity in CLL cells; however, the underlying mechanisms leading to this disease remain largely unknown and were a subject of this grand application. To prevent persistent NF-κB activation, a tight control is required. Whereas linkage with polyubiquitin chains via lysine-48 results in proteasomal degradation of target proteins, lysine-63-linked polyubiquitin chains have non-degradative, regulatory functions and serve in the recruitment of various kinase complex platforms. Ubiquitination is a reversible process mediated by deubiquitinating enzymes, such as CYLD and A20, which prevent persistent NF-κB activation by deubiquitinating target proteins. CYLD acts as a negative regulator of the NF-κB pathway by removing lysine-63-linked ubiquitin chains from its target proteins thereby regulating diverse biological functions, such as immune-cell-development, activation, inflammation and tumorigenesis. Previously, we have identified a short isoform of CYLD, termed sCYLD, encoded by a natural splice variant of the Cyld mRNA that retains deubiquitinating activity but lacks the domain for TRAF2 and NEMO, required to dampen NF-κB activation. Mice lacking (FL)-Cyld but overexpressing sCYLD demonstrate enlarged lymphoid organs resulting from an expanded B2 B-cell compartment. Similar to CYLD, A20 (TNFAIP3) is capable of removing lysine-63, but also lysine-48-linked ubiquitin chains from its target proteins. Others and we could show that B-cell-specific deletion of A20 results in sustained canonical NF-κB activity and predisposes mice to autoimmunity. During the time of this application we could show that mice with accelerated activation of canonical NF-κB activation, driven by sCYLD overexpression in B cells, spontaneously develop a CD5+ B-cell lymphoproliferative disorder while mice with a complete lack of CYLD did not develop signs of this disease, indicating a sCYLD dependent phenotype. Further enhancement of canonical NF-κB activation, achieved by additional B-cell-specific deletion of A20, reinforced clonal accumulation of CD5+ B cells, ultimately leading to a late-onset CLL-like disease, recapitulating hallmarks of human CLL. Mice with A20 deletion specifically in B cells (A20BKO mice) were used to achieve sustained activation of canonical NF-κB signaling; in CLL patients, this activation occurs through other mechanisms, including BCR or microenvironmental activation. We further found that a substantial number of CLL patient samples express sCYLD, strongly implicating a role for it in human B-CLL. We propose that our new CLL-like mouse model represents an appropriate tool for studying ubiquitination-driven canonical NF-κB activation in CLL. Thus, inhibition of alternative splicing of this negative regulator is essential for preventing NF-κB-driven clonal CD5+ B-cell expansion and ultimately CLL-like disease.

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