title: Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice.
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.
authors: Division of Clinical Studies, Institute of Cancer Research, London SM2 5NG, UK.
authors: Veronica S
authors: VS
authors: Gil
authors: Department of Pathology & Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.|Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
authors: Govind
authors: 0000-0001-6250-048X
authors: G
authors: Bhagat
authors: Division of Molecular Pathology, Institute of Cancer Research, London SM2 5NG, UK.
authors: Louise
authors: L
authors: Howell
authors: Department of Pathology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.|Institute for Cancer Genetics, Columbia University, New York, NY 10032, USA.
authors: Jiyuan
authors: J
authors: Zhang
authors: Division of Hematopathology, Sylvester Cancer Center, University of Miami, Miami, FL 33136, USA.
authors: Chae H
authors: CH
authors: Kim
authors: Division of Molecular Pathology, Institute of Cancer Research, London SM2 5NG, UK.
authors: Sven
authors: S
authors: Stengel
authors: Division of Hematopathology, Sylvester Cancer Center, University of Miami, Miami, FL 33136, USA.
authors: Francisco
authors: F
authors: Vega
authors: Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA.
authors: Arthur
authors: A
authors: Zelent
authors: Department of Biological and Environmental Sciences, Faculty of Natural Sciences, University of Stirling, Stirling FK9 4LA, UK kevin.petrie@stir.ac.uk.
authors: Kevin
authors: 0000-0002-9805-9152
authors: K
authors: Petrie
mesh_terms: D000107:Acetylation; D000818:Animals; D001402:B-Lymphocytes / Q000201:enzymology* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain / Q000235:genetics; D006367:HeLa Cells; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008822:Mice, Transgenic; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D051560:Proto-Oncogene Proteins c-bcl-6; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C486544:HDAC9 protein, human; D006655:Histone Deacetylases
keywords: HDAC9; Lymphoma; Transgenic mouse