Abstract

Histone Deacetylase 9 (HDAC9) is a class IIa enzyme that, within the hematopoietic system, is preferentially expressed in the B-cell lineage. Previously we have observed that, compared with normal cellular counterparts, expression of HDAC9 appears deregulated in B-lymphoid tumors (Petrie et al., JBC 278: 16059, 2003 and unpublished results). To examine the role of HDAC9 in B-cell transformation we generated a 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). We demonstrate that from six months of age (6–12 months), Eμ-HDAC9 transgenic mice displayed splenomegaly in a statistically significant fraction of cases (3/17, 18%), which was associated with histopathologic and immunophenotypic evidence of lymphoproliferative disease (LPD) (p<0.0001). Later in life (12 to 23 months of age), 24% (19/78) of Eμ-HDAC9 mice developed a spectrum of mature clonal B-cell lymphoproliferations including monoclonal B-cell lymphocytosis (MBL, 12/78, 15%), splenic marginal zone lymphoma (SMZL, 4/78, 5%) and diffuse large B-cell lymphoma (DLBCL, 3/78, 4%). In contrast, a low background incidence of these malignancies (2%) was observed in control mice (p = 0.0008). Importantly, the HDAC9 gene is located within chromosomal region 7p21, which is a common target of frequent genomic gains in B-cell non-Hodgkin lymphoma (B-NHL) cases and B-NHL cell lines. Consistently, copy number gains in the 7p21.1 chromosomal region were found in 25/79 (32%) primary DLBCL cases analyzed (including one B-NHL patient with a copy number gain only within the 5' end of the HDAC9 gene). Mechanism underlying the role of HDAC9 in lymphomagenesis appears to involve deacetylation of both p53 (leading to deactivation of p53) and BCL6 (leading to activation of BCL6), consistent with a role of a general hypoacetylated state in B-NHL pathogenesis, which is underscored by recently identified inactivating mutations in a number of key histone acetyltransferases. In summary, aberrant expression of HDAC9 leads to the development of B-cell lymphoproliferations, including germinal center (GC) and post-GC lymphomas, showing similarities with those occurring in humans. These findings have relevant therapeutic implications in view of current attempts to use HDAC inhibitors as anti-lymphoma drugs.