BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy.
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.
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Leandro C
LC
Cerchietti
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Katerina
K
Hatzi
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Eloisi
E
Caldas-Lopes
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Shao Ning
SN
Yang
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Maria E
ME
Figueroa
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Ryan D
RD
Morin
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Martin
M
Hirst
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Lourdes
L
Mendez
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Rita
R
Shaknovich
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Philip A
PA
Cole
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Kapil
K
Bhalla
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Randy D
RD
Gascoyne
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Marco
M
Marra
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Gabriela
G
Chiosis
Hematology and Oncology Division, and Department of Pharmacology, Weill Cornell Medical College, New York, New York, USA. Department of Molecular Pharmacology and Chemistry, Sloan-Kettering Institute, New York, New York, USA. Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. Department of Pathology, Weill Cornell Medical College, New York, New York, USA. Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. The University of Kansas Cancer Center, Kansas University Medical Center, Kansas City, Kansas, USA. Centre for Lymphoid Cancers and the Departments of Pathology and Experimental Therapeutics, British Columbia Cancer Agency, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada.
Ari
A
Melnick
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D050881:E1A-Associated p300 Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D023041:Xenograft Model Antitumor Assays
C092009:BAG6 protein, human; C084103:BCL6 protein, human; D004268:DNA-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D018832:Molecular Chaperones; D051560:Proto-Oncogene Proteins c-bcl-6; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human