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Abstract 1433: Mice Overexpressing Histone Deacetylase 9 Display Abnormal B Cell Development and Proliferation.

Gil, Veronica S., Petrie, Kevin, Chornet, Manuel Boix, Howell, Louise, Sebire, Neil J. and Zelent, Arthur (2006) Abstract 1433: Mice Overexpressing Histone Deacetylase 9 Display Abnormal B Cell Development and Proliferation. Blood, 108 (11). p. 1433. ISSN 0006-4971

Item Type: Article

Abstract

Histone acetylation plays a key role in regulating chromatin structure and gene expression. The activities of histone deacetylases (HDAC), enzymes that remove acetyl groups from lysines located at the amino-terminal tails of core histones, have been implicated in the pathogenesis of hematological malignancies. Consequently, inhibitors of these enzymes (HDACi) are considered an important new class of drugs for use in anti-cancer therapy and are now in various stages of development and clinical trials. For example, depsipeptide has now been granted a fast track designation by the FDA for development as a treatment for CTCL. To date, eleven HDACs have been identified and grouped on the basis of sequence homology to class I (HDACs 1–3 and 8), IIa (4, 5, 7 and 9) and IIb (6, 10 and 11). Depsipeptide and other currently used HDACi lack class and enzyme specificities. Additionally, the contribution of each HDAC to the pathogenesis of a given malignant disease is poorly understood. Improvements in HDACi specificities, together with advances in the understanding of the roles that individual HDACs play in normal hematopoiesis and distinct hematological neoplasms, are required for an effective use of these agents in anti-cancer therapies. We have previously identified and characterized HDAC9 as a class IIa enzyme that within the hematopoietic system is preferentially expressed in the lymphoid lineage. HDAC9 appears to be overexpressed in B lymphoid malignancies and associates at physiological levels with the BCL6 oncoprotein (
Petrie et al, JBC 278:16059–72, 2003), a transcriptional repressor implicated in the pathogenesis of non-Hodgkin’s lymphoma, suggesting a role for this chromatin modifying enzyme in B-cell transformation. In order to examine the function of HDAC9 in lymphoid development and cancer, we have generated transgenic mice that express the protein throughout the B lymphoid compartment under the control of the immunoglobulin heavy chain enhancer (Eμ). Initial data show that at an average of seven months these mice display splenomegaly and alterations to the splenic and bone marrow lymphoid populations. The presence of immature lymphocytes was also detected in peripheral blood. Consistent with these results and the above hypothesis, knockdown of HDAC9 results in strong inhibition of cell growth. These data indicate that aberrant expression of HDAC9 confers a proliferative advantage and leads to a phenotype resembling a pre-malignant condition.

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More Information

Uncontrolled Keywords: b cell development, cancer, enzymes, hdac9 gene, hematologic neoplasms, histone deacetylase, histone deacetylase inhibitors, histones, immunoglobulin heavy chains, lymphoid neoplasm, malignant
Depositing User: Kevin Petrie

Identifiers

Item ID: 15818
Identification Number: https://doi.org/10.1182/blood.V108.11.1433.1433
ISSN: 0006-4971
URI: http://sure.sunderland.ac.uk/id/eprint/15818
Official URL: http://dx.doi.org/10.1182/blood.V108.11.1433.1433

Users with ORCIDS

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

Catalogue record

Date Deposited: 22 Mar 2023 15:41
Last Modified: 22 Mar 2023 15:41

Contributors

Author: Kevin Petrie ORCID iD
Author: Veronica S. Gil
Author: Manuel Boix Chornet
Author: Louise Howell
Author: Neil J. Sebire
Author: Arthur Zelent

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences

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