TitleBCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy.
Publication TypeJournal Article
Year of Publication2010
AuthorsCerchietti, Leandro C., Hatzi Katerina, Caldas-Lopes Eloisi, Yang Shao Ning, Figueroa Maria E., Morin Ryan D., Hirst Martin, Mendez Lourdes, Shaknovich Rita, Cole Philip A., Bhalla Kapil, Gascoyne Randy D., Marra Marco, Chiosis Gabriela, and Melnick Ari
JournalJ Clin Invest
Date Published2010 Dec 01
KeywordsAnimals, Antineoplastic Combined Chemotherapy Protocols, Cell Line, Tumor, DNA-Binding Proteins, E1A-Associated p300 Protein, Female, Histone Deacetylase Inhibitors, Humans, Lymphoma, Large B-Cell, Diffuse, Male, Mice, Mice, SCID, Molecular Chaperones, Proto-Oncogene Proteins c-bcl-6, Xenograft Model Antitumor Assays

<p>B cell lymphoma 6 (BCL6), which encodes a transcriptional repressor, is a critical oncogene in diffuse large B cell lymphomas (DLBCLs). Although a retro-inverted BCL6 peptide inhibitor (RI-BPI) was recently shown to potently kill DLBCL cells, the underlying mechanisms remain unclear. Here, we show that RI-BPI induces a particular gene expression signature in human DLBCL cell lines that included genes associated with the actions of histone deacetylase (HDAC) and Hsp90 inhibitors. BCL6 directly repressed the expression of p300 lysine acetyltransferase (EP300) and its cofactor HLA-B-associated transcript 3 (BAT3). RI-BPI induced expression of p300 and BAT3, resulting in acetylation of p300 targets including p53 and Hsp90. Induction of p300 and BAT3 was required for the antilymphoma effects of RI-BPI, since specific blockade of either protein rescued human DLBCL cell lines from the BCL6 inhibitor. Consistent with this, combination of RI-BPI with either an HDAC inhibitor (HDI) or an Hsp90 inhibitor potently suppressed or even eradicated established human DLBCL xenografts in mice. Furthermore, HDAC and Hsp90 inhibitors independently enhanced RI-BPI killing of primary human DLBCL cells in vitro. We also show that p300-inactivating mutations occur naturally in human DLBCL patients and may confer resistance to BCL6 inhibitors. Thus, BCL6 repression of EP300 provides a basis for rational targeted combinatorial therapy for patients with DLBCL.</p>

Alternate JournalJ Clin Invest
PubMed ID21041953
PubMed Central IDPMC2993589
Grant ListK08 CA127353 / CA / NCI NIH HHS / United States
GM62437 / GM / NIGMS NIH HHS / United States
R01 GM062437 / GM / NIGMS NIH HHS / United States
N01CO12400 / CA / NCI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States
N01-CO-12400 / CO / NCI NIH HHS / United States
R01 CA143032 / CA / NCI NIH HHS / United States
R01 CA155226 / CA / NCI NIH HHS / United States
R37 GM062437 / GM / NIGMS NIH HHS / United States
R01-CA104348 / CA / NCI NIH HHS / United States