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

Citation

Gil V, Bhagat G, Howell L, Zhang J, Kim CH, Stengel S, Vega F, Zelent A & Petrie K (2016) Deregulated expression of HDAC9 in B cells promotes development of lymphoproliferative disease and lymphoma in mice. Disease Models and Mechanisms, 9 (12), pp. 1483-1495. https://doi.org/10.1242/dmm.023366

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 andHDAC9copy 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 anHDAC9transgene throughout B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eμ). Here, we report that theEμ-HDAC9GEM 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 ofEμ-HDAC9tumors 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.

Keywords
HDAC9; Lymphoma; Transgenic mouse

Journal
Disease Models and Mechanisms: Volume 9, Issue 12

• Gil-etal-DMM-2016.pdf