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

Autor: Kevin Petrie, Govind Bhagat, Francisco Vega, Louise Howell, Sven Stengel, Veronica Gil, Jiyuan Zhang, Arthur Zelent, Chae H. Kim
Rok vydání: 2016
Předmět:
0301 basic medicine
Lymphoma
B-Cell
Lymphoma
Gene Rearrangement
B-Lymphocyte
Heavy Chain
Neuroscience (miscellaneous)
lcsh:Medicine
Medicine (miscellaneous)
Mice
Transgenic
Biology
Histone Deacetylases
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
Immunology and Microbiology (miscellaneous)
Transgenic mouse
immune system diseases
hemic and lymphatic diseases
lcsh:Pathology
medicine
Animals
Humans
Epigenetics
Splenic marginal zone lymphoma
sub_healthsciences
B-Lymphocytes
Gene Expression Profiling
Cell Cycle
lcsh:R
HDAC9
Germinal center
Acetylation
Epigenome
medicine.disease
BCL6
Lymphoproliferative Disorders
Gene Expression Regulation
Neoplastic
Repressor Proteins
030104 developmental biology
Immunology
Proto-Oncogene Proteins c-bcl-6
Cancer research
Histone deacetylase
Tumor Suppressor Protein p53
sub_biomedicalsciences
Research Article
HeLa Cells
lcsh:RB1-214
Zdroj: Disease Models & Mechanisms, Vol 9, Iss 12, Pp 1483-1495 (2016)
Disease Models & Mechanisms
ISSN: 1754-8411
1754-8403
DOI: 10.1242/dmm.023366
Popis: 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.
Summary: This study demonstrates that aberrant expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma through altering expression of genes involved in the cell cycle and survival, and modulating the activity of key B-lineage factors such as BCL6 and p53.
Databáze: OpenAIRE
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