ArticleThe Journal of clinical investigation2010
BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy.
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Article in The Journal of clinical investigation, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 74 papers.
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74 citing papers in PubMed, 120 citations in OpenAlex.
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- Altered pathways and targeted therapy in double hit lymphoma.Journal of hematology & oncology · 2022Review
- Dysregulation of miRNAs in DLBCL: Causative Factor for Pathogenesis, Diagnosis and Prognosis.Diagnostics (Basel, Switzerland) · 2021Review
- Progress toward B-Cell Lymphoma 6 BTB Domain Inhibitors for the Treatment of Diffuse Large B-Cell Lymphoma and Beyond.Journal of medicinal chemistry · 2021Article
- Interplay between cofactors and transcription factors in hematopoiesis and hematological malignancies.Signal transduction and targeted therapy · 2021Review
- Epigenetic, Metabolic, and Immune Crosstalk in Germinal-Center-Derived B-Cell Lymphomas: Unveiling New Vulnerabilities for Rational Combination Therapies.Frontiers in cell and developmental biology · 2021Review
- Epigenetic Mechanisms of Therapy Resistance in Diffuse Large B Cell Lymphoma (DLBCL).Current cancer drug targets · 2021Review
- Epigenetic Mechanisms in Leukemias and Lymphomas.Cold Spring Harbor perspectives in medicine · 2020Review
- Genetics and epigenetics of leukemia and lymphoma: from knowledge to applications, meeting report of the Josep Carreras Leukaemia Research Institute.Hematological oncology · 2020Review
- BCL-6 suppresses miR-142-3p/5p expression in SLE CD4Cellular & molecular immunology · 2020Article
- Role of HDACs in normal and malignant hematopoiesis.Molecular cancer · 2020Review
14 more citing papers are in PubMed but not listed here.
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Authors and funding
15 authors at 5 institutions in 2 countries.
Leandro C CerchiettiHematology 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 HatziHematology 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 Caldas-LopesHematology 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 YangHematology 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 FigueroaHematology 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 MorinHematology 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 HirstHematology 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 MendezHematology 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 ShaknovichHematology 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 ColeHematology 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 BhallaHematology 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 GascoyneHematology 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 MarraHematology 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 ChiosisHematology 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 MelnickHematology 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.
Cornell University · USUniversity of British Columbia · CAMemorial Sloan Kettering Cancer Center · USJohns Hopkins University · USUniversity of Kansas · US
Funding
Protein Acylation and Methylation Mechanisms_Administrative SupplementR37GM062437 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI COLE, PHILIP A · 2013 to 2022
$4.1MMechanisms &Inhibition of Histone AcetyltransferasesR01GM062437 · NIGMS · JOHNS HOPKINS UNIVERSITY · PI COLE, PHILIP A · 2001 to 2012
$3.8MMolecular Targeting of Diffuse Large B-cell LymphomaR01CA143032 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI MELNICK, ARI M. · 2010 to 2014
$2.8MTranscriptional silencing by the BCL6 oncoproteinR01CA104348 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI MELNICK, ARI M. · 2004 to 2014
$2.6MTargeting the heat shock response for the therapy of DLBCLR01CA155226 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI CHIOSIS, GABRIELA, MELNICK, ARI M. · 2011 to 2015
$2.5MEpigenetic Mechanisms of Lymphomagenesis.K08CA127353 · NCI · WEILL MEDICAL COLL OF CORNELL UNIV · PI SHAKNOVICH, RITA · 2008 to 2012
$693kNCI NIH HHS K08 CA127353NCI NIH HHS N01 CO012400NCI NIH HHS N01-CO-12400NCI NIH HHS R01 CA104348NCI NIH HHS R01-CA104348NCI NIH HHS R01 CA143032NCI NIH HHS R01 CA155226NIGMS NIH HHS GM62437NIGMS NIH HHS R01 GM062437NIGMS NIH HHS R37 GM062437
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.
Indexed as
AnimalsAntineoplastic Combined Chemotherapy ProtocolsCell Line, TumorDNA-Binding ProteinsE1A-Associated p300 ProteinFemaleHistone Deacetylase InhibitorsHumansLymphoma, Large B-Cell, DiffuseMaleMiceMice, SCIDMolecular ChaperonesProto-Oncogene Proteins c-bcl-6Xenograft Model Antitumor AssaysBAG6 protein, humanBCL6 protein, humanDNA-Binding ProteinsE1A-Associated p300 ProteinEP300 protein, humanHistone Deacetylase InhibitorsMolecular ChaperonesProto-Oncogene Proteins c-bcl-6
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