Related Experiment Video
Updated: Jun 7, 2026
In Vitro Differentiation Model of Human Normal Memory B Cells to Long-lived Plasma Cells
Published on: January 20, 2019
BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial
Leandro C Cerchietti1, Katerina Hatzi1, Eloisi Caldas-Lopes1
1Hematology 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.
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.
Insights
A novel BCL6 inhibitor, RI-BPI, kills lymphoma cells by inducing p300 and BAT3, enhancing acetylation of targets like p53. Combining RI-BPI with HDAC or Hsp90 inhibitors shows potent anti-lymphoma effects.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- B cell lymphoma 6 (BCL6) is a key oncogene in diffuse large B cell lymphomas (DLBCLs).
- A BCL6 peptide inhibitor (RI-BPI) demonstrates potent killing of DLBCL cells, but its mechanism is not fully understood.
- Understanding RI-BPI's mechanism is crucial for developing targeted therapies for DLBCL.
Purpose of the Study:
- To elucidate the molecular mechanisms by which RI-BPI exerts its anti-lymphoma effects.
- To investigate the role of p300 and BAT3 in RI-BPI's activity.
- To explore the potential of combining RI-BPI with HDAC or Hsp90 inhibitors for DLBCL treatment.
Main Methods:
- Analysis of gene expression signatures induced by RI-BPI in human DLBCL cell lines.
- Investigation of BCL6's direct repression of EP300 and BAT3 expression.
- Assessment of p300 and BAT3 induction and subsequent target acetylation (p53, Hsp90).
- Evaluation of the necessity of p300 and BAT3 for RI-BPI's anti-lymphoma activity.
- Testing the efficacy of RI-BPI in combination with HDAC or Hsp90 inhibitors in DLBCL xenograft models and primary cells.
Main Results:
- RI-BPI induces a gene expression signature linked to HDAC and Hsp90 inhibitors.
- BCL6 directly represses EP300 and BAT3; RI-BPI treatment leads to their induction and subsequent acetylation of p53 and Hsp90.
- Induction of p300 and BAT3 is essential for RI-BPI's anti-lymphoma effects, as blocking them rescues DLBCL cells.
- Combination therapy with RI-BPI and HDAC or Hsp90 inhibitors effectively eradicated DLBCL xenografts in mice.
- HDAC and Hsp90 inhibitors enhanced RI-BPI's killing of primary DLBCL cells in vitro.
- Naturally occurring p300-inactivating mutations in DLBCL patients may confer resistance to BCL6 inhibitors.
Conclusions:
- BCL6 repression of EP300 provides a mechanistic basis for RI-BPI's action.
- The induction of p300 and BAT3, leading to target acetylation, is critical for RI-BPI's anti-lymphoma activity.
- Combination therapy with RI-BPI and HDAC or Hsp90 inhibitors represents a promising strategy for DLBCL treatment.
- Understanding resistance mechanisms, such as p300 mutations, is important for patient stratification and treatment optimization.
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against specific...
02:50Combination Therapies and Personalized Medicine
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...
02:23Abnormal Proliferation