Histone deacetylase 3 (HDAC3) deacetylates selective lysine residues on histone H3 and H4 to control chromatin structure and repress gene expression. During murine B cell development, Hdac3 is required for efficient V-D-J recombination, but once past this developmental stage B cells lacking Hdac3 survive, but fail to undergo a productive germinal center reaction in response to antigen. Rather, these cells accumulate in the ?light zone? of the germinal center where the phenotype and gene expression pattern of Hdac3-/- B cells matched those of Foxo1-/- B cells. This is remarkable because Foxo1 recruits Hdac3. While Foxo1 is typically thought of as a transcriptional activator, in germinal center B cells, genes identified in ChIP-seq studies as bound by Foxo1 were up-regulated when Foxo1 was deleted. Moreover, in 10% of the lymphoma derived from the germinal center Foxo1 is activated by mutations that allow it to escape negative regulation by Akt. The convergence between Foxo1 and Hdac3, suggested that Hdac3 might play a key role in Foxo1-dependent diffuse large B cell lymphoma (DLBCL). Treatment of 8 different DLBCL cell lines with a selective Hdac3 inhibitor showed that only the cells with activating mutations in Foxo1 were sensitive, whereas cells containing other common mutations such as translocation of BCL6 were not. Moreover, this inhibitor caused activation of genes that were bound by Foxo1 in ChIP-exo studies. These preliminary studies lead to the hypothesis that Hdac3 is a viable therapeutic target in Foxo1 mutant diffuse large B cell lymphoma. This hypothesis will be directly tested by creating mice containing B cell lymphoma driven by mutant Foxo1 and then deleting Hdac3. In addition, we will fine map the domain in Foxo1 required for recruitment of Hdac3 and make mutants that cannot bind to Hdac3 to test whether recruitment of Hdac3 is required for lymphomagenesis and lymphoma cell survival. We will also use cutting-edge genomic methods such as PRO-seq to define the mechanism by which Hdac3 recruitment by Foxo1 regulates gene expression. This comprehensive approach will conclusively define whether Hdac3 is a therapeutic target in B cell lymphoma and may spur further development of selective inhibitors of Hdac3 and/or Foxo1.
Histone deacetylase 3 (Hdac3) is a key factor that controls the structure of our DNA and the expression of genes. This application will directly test if inhibiting this enzyme with a drug is a viable therapeutic strategy for a deadly type of lymphoma that contains a specific mutation. If so, this approach could lead to cures for this lymphoma, which is resistant to normal chemotherapy.
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