Abstract 81: Deregulated expression of HDAC9 in B cells leads to the development of lymphoproliferative disease and lymphoma

Abstract

Abstract Aberrant epigenetics leading to changes in chromatin structure and patterns of gene expression is an important factor in cancer pathogenesis. Histone Deacetylase 9 (HDAC9) is a class IIa chromatin-modifying enzyme that, within the haematopoietic system, is preferentially expressed in the B-cell lineage. Furthermore, HDAC9 expression is deregulated in B-lymphoid malignancies. To examine the role of HDAC9 in malignant B-cell transformation, we generated an in vivo mouse model that constitutively expresses human HDAC9 from early stages of B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eµ). In this study, we demonstrate that from an average of six months of age, Eµ-HDAC9 transgenic mice displayed splenomegaly and immunophenotypic features that resemble lymphoproliferative disease (LPD) in spleen. Later on in life, up to twenty-three months of age, 24% (19 out of 78) of Eµ-HDAC9 mice developed mature B-cell neoplasms such as splenic marginal zone lymphoma (SMZL) and aggressive diffuse large B-cell lymphoma (DLBCL) that could represent a progression stage of the observed lymphoproliferative disease (LPD) and monoclonal B-cell lymphocytosis (MBL). In contrast, a low background incidence of these malignancies was observed in control mice, 2% (1 out of 46) (p = 0.0008). The molecular pathogenesis of the Eµ-HDAC9 B-cell tumors seems to involve activation-deactivation of the BCL6-p53 axis by HDAC9 influenced deacetylation thus affecting DNA repair and cell cyle progression in germinal centre (GC) during immune response. Consistently, ZFN-mediated HDAC9-knockout results in cell cycle changes leading to strong inhibition of cell growth in vitro. In summary, aberrant expression of HDAC9 leads to the development of lymphoproliferative disorders, including GC and post-GC lymphomas, demonstrating an oncogenic role for HDAC9 in B-cells and highlighting its importance as a therapeutic target. Citation Format: Veronica S. Gil. Deregulated expression of HDAC9 in B cells leads to the development of lymphoproliferative disease and lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 81. doi:10.1158/1538-7445.AM2014-81