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Diffuse Large B-Cell Lymphoma (DLBCL)

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoid malignancy that accounts for up to 40% of non-Hodgkin’s lymphoma. Despite recent advances in our understanding of the pathogenesis of DLBCL, standard-of-care treatments are ineffective for one-third of patients. DLBCL is characterized by epigenetic dysregulation and patients have recurrent mutations in numerous transcription regulatory factors. For DLBCL, we are especially focused on the role of HDAC3, which deacetylates both histone and non-histone substrates in conjunction with its co-factors, NCOR and SMRT. The transcription factor B cell lymphoma b (BCL6) recruits SMRT and HDAC3 to trigger B cell lymphoma, we selectively deleted Hdac3 in maturing B cells in mice expecting a BCL6-/--like phenotype. However, our preliminary data show that inactivation of Hdac3 more closely mimicked the deletion of the transcription factor Foxo1, including a block at the same stage in germinal center B cell development and significant overlap in genes up-regulated upon loss of the transcription factor Foxo1. We are applying our dTAG pipeline to targets in this pathway.