UBR5 HECT domain mutations identified in mantle cell lymphoma control maturation of B cells

Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B cells. Disruption of these pathways can result in malignant transformation. Recently, next-generation s...

Full description

Saved in:
Bibliographic Details
Published in:Blood 2020-07, Vol.136 (3), p.299-312
Main Authors: Swenson, Samantha A., Gilbreath, Tyler J., Vahle, Heather, Hynes-Smith, R. Willow, Graham, Jared H., Law, Henry C.-H., Amador, Catalina, Woods, Nicholas T., Green, Michael R., Buckley, Shannon M.
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - enzymology
Humans
Immunobiology and Immunotherapy
Lymphoma, Mantle-Cell - enzymology
Lymphoma, Mantle-Cell - genetics
Mice
Mice, Mutant Strains
Mutation
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
Protein Domains
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Coordination of a number of molecular mechanisms including transcription, alternative splicing, and class switch recombination are required to facilitate development, activation, and survival of B cells. Disruption of these pathways can result in malignant transformation. Recently, next-generation sequencing has identified a number of novel mutations in mantle cell lymphoma (MCL) patients including mutations in the ubiquitin E3 ligase UBR5. Approximately 18% of MCL patients were found to have mutations in UBR5, with the majority of mutations within the HECT domain of the protein that can accept and transfer ubiquitin molecules to the substrate. Determining if UBR5 controls the maturation of B cells is important to fully understand malignant transformation to MCL. To elucidate the role of UBR5 in B-cell maturation and activation, we generated a conditional mutant disrupting UBR5′s C-terminal HECT domain. Loss of the UBR5 HECT domain leads to a block in maturation of B cells in the spleen and upregulation of proteins associated with messenger RNA splicing via the spliceosome. Our studies reveal a novel role of UBR5 in B-cell maturation by stabilization of spliceosome components during B-cell development and suggests UBR5 mutations play a role in MCL transformation. •Using a novel mouse model mimicking MCL patient mutations, the loss of HECT domain of UBR5 causes alterations in B-cell development.•UBR5 mutations lead to stabilization of UBR5 and spliceosome components. [Display omitted]
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2019002102