Dissecting the Role Ubiquitin E3 Ligase UBR5 in Lymphomagenesis

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ABSTRACT Mantle cell lymphoma (MCL) is a rare and aggressive non-Hodgkin’s lymphoma. Unfortunately limited therapies for MCL are currently available suggesting a need to further unravel molecular mechanisms regulating transformation and progression of the disease. The majority of MCL patients have a t(11;14) translocation leading to overexpression of CyclinD1 resulting in extensive proliferation and block in differentiation originating in the mantle zone of the lymph node, however additional mutations are necessary for transformation. Next generation sequencing has identified a number of novel mutations in MCL patients including the ubiquitin E3 ligase UBR5. E3 ubiquitin ligases serve as the substrate-recognizing component for protein degradation by the ubiquitin proteasome system. In a cohort of 196 MCL patients UBR5 was the 3rd most frequently mutated gene and ~60% of the mutations were found within the HECT domain of UBR5, which can accept and transfer ubiquitin molecules to the substrate. In order to understand the role of UBR5 HECT domain in B-lymphoid development we generated a conditional mouse using novel CRISPR/Cas 9 technology. Loss of the HECT domain leads to a block in pre-germinal center B cells in the spleen with a reduction of both B1 and marginal B cell subsets. In addition, follicular B cells in the spleen are phenotypically abnormal and fail to terminally differentiate to anti-body secreting plasma cells. Proteomic studies reveal up-regulation of proteins associated with mRNA splicing via the spliceosome in B cells lacking the HECT domain of UBR5. These studies suggest that 1) cooperation of UBR5 mutations along with expression of cyclinD1 may led to disease progression of mantle cell lymphoma (Aim 1), 2) understanding molecular mechanism of UBR5 mutations could provide potential therapeutic targets in MCL (Aim 2), and 3) aberrant expression of U5 spliceosome proteins block B cell maturation and promote lymphomagenesis (Aim 3). In this application we propose studies to understand the role of UBR5 and its interacting proteins in B-cell lymphomagenesis and define molecular pathways regulated by UBR5 in B-cells. Our goal of the proposed studies is to provide insights to mantle cell lymphoma transformation, progression and potential future therapeutics targets.