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Title: Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice [HDAC9 transgenic]      
keywords:
Transcriptome or Gene expression
ID:
PRJNA354538
description:
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. Overall design: FLAG-epitope-tagged full-length human HDAC9 cDNA was cloned into the pEμSR vector, placing the HDAC9-sequence-containing oligonucleotide cassette downstream of the immunoglobulin heavy chain (IgH) enhancer (Eμ) and the SRα potent promoter (Bodrug et al., 1994). The Eμ-HDAC9 transgenic fragment was isolated from the vector by enzymatic digestion using the NotI restriction sites and injected into B6CBAF1 pronuclei. Mice were backcrossed and maintained in a C57BL/6 background to generate three transgenic lines: 1468, 1469 and 1839. PCR genotyping was performed using SV40 primers: F: 5′-GGAACTGATGAATGGGAGCA-3′ and R: 5′-GCAGTGCAGCTTTTTCCTTT-3′. Mice were housed and maintained in accordance with UK Home Office regulations. Animals were monitored and analyzed from birth to 23 months of age and sacrificed if showing signs of illness. Statistical analysis was performed using Prism (GraphPad Software). Kaplan–Meier cumulative survival and the log-rank (Mantel–Cox) test were used to determine tumor-free survival and the χ2 test was used to compare B-NHL incidence in HDAC9 mice versus wild-type controls. P<0.05 was considered statistically significant. All experimental protocols were monitored and approved by The Institute of Cancer Research Animal Welfare and Ethical Review Body, in compliance with guidelines specified by the UK Home Office Animals (Scientific Procedures) Act 1986 and the United Kingdom National Cancer Research Institute guidelines for the welfare of animals in cancer research (Workman et al., 2010). ARRIVE guidelines were applied when reporting in vivo experiments (Kilkenny et al., 2010).
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA354538
authentication:
none
authorization:
none
ID:
pmid:27799148
name:
Mus musculus
ncbiID:
ncbitax:10090
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject