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BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2010 Dec 01; Vol. 120 (12), pp. 4569-82. Date of Electronic Publication: 2010 Nov 01. - Publication Year :
- 2010
-
Abstract
- 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.
- Subjects :
- Animals
Cell Line, Tumor
DNA-Binding Proteins genetics
DNA-Binding Proteins metabolism
E1A-Associated p300 Protein genetics
E1A-Associated p300 Protein metabolism
Female
Histone Deacetylase Inhibitors pharmacology
Humans
Lymphoma, Large B-Cell, Diffuse metabolism
Lymphoma, Large B-Cell, Diffuse pathology
Male
Mice
Mice, SCID
Molecular Chaperones genetics
Molecular Chaperones metabolism
Proto-Oncogene Proteins c-bcl-6
Xenograft Model Antitumor Assays
Antineoplastic Combined Chemotherapy Protocols pharmacology
DNA-Binding Proteins antagonists & inhibitors
E1A-Associated p300 Protein antagonists & inhibitors
Lymphoma, Large B-Cell, Diffuse drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 120
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 21041953
- Full Text :
- https://doi.org/10.1172/JCI42869