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Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice.

Gil, Veronica S, Bhagat, Govind, Howell, Louise, Zhang, Jiyuan, Kim, Chae H, Stengel, Sven, Vega, Francisco, Zelent, Arthur and Petrie, Kevin (2016) Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice. Disease models & mechanisms, 9 (12). pp. 1483-1495. ISSN 1754-8411

Item Type: Article

Abstract

Histone deacetylase 9 (HDAC9) is expressed in B cells, and its overexpression has been observed in B-lymphoproliferative disorders, including B-cell non-Hodgkin lymphoma (B-NHL). We examined HDAC9 protein expression and copy number alterations in primary B-NHL samples, identifying high HDAC9 expression among various lymphoma entities and HDAC9 copy number gains in 50% of diffuse large B-cell lymphoma (DLBCL). To study the role of HDAC9 in lymphomagenesis, we generated a genetically engineered mouse (GEM) model that constitutively expressed an HDAC9 transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that the Eμ-HDAC9 GEM model develops splenic marginal zone lymphoma and lymphoproliferative disease (LPD) with progression towards aggressive DLBCL, with gene expression profiling supporting a germinal center cell origin, as is also seen in human B-NHL tumors. Analysis of Eμ-HDAC9 tumors suggested that HDAC9 might contribute to lymphomagenesis by altering pathways involved in growth and survival, as well as modulating BCL6 activity and p53 tumor suppressor function. Epigenetic modifications play an important role in the germinal center response, and deregulation of the B-cell epigenome as a consequence of mutations and other genomic aberrations are being increasingly recognized as important steps in the pathogenesis of a variety of B-cell lymphomas. A thorough mechanistic understanding of these alterations will inform the use of targeted therapies for these malignancies. These findings strongly suggest a role for HDAC9 in B-NHL and establish a novel GEM model for the study of lymphomagenesis and, potentially, preclinical testing of therapeutic approaches based on histone deacetylase inhibitors.

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More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 12446
Identification Number: https://doi.org/10.1242/dmm.023366
ISSN: 1754-8411
URI: http://sure.sunderland.ac.uk/id/eprint/12446
Official URL: https://dmm.biologists.org/content/9/12/1483

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 18 Aug 2020 19:09
Last Modified: 23 Nov 2020 18:41

Contributors

Author: Kevin Petrie ORCID iD
Author: Veronica S Gil
Author: Govind Bhagat
Author: Louise Howell
Author: Jiyuan Zhang
Author: Chae H Kim
Author: Sven Stengel
Author: Francisco Vega
Author: Arthur Zelent

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences > Health Sciences

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