Dissecting the Role Ubiquitin E3 Ligase UBR5 in Lymphomagenesis

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.

Grant Number: 5R37CA262635-05
NIH Institute/Center: NIH
Principal Investigator: Shannon Buckley