BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy

Leandro C. Cerchietti, Katerina Hatzi, Eloisi Caldas-Lopes, Shao Ning Yang, Maria Figueroa, Ryan D. Morin, Martin Hirst, Lourdes Mendez, Rita Shaknovich, Philip A. Cole, Kapil Bhalla, Randy D. Gascoyne, Marco Marra, Gabriela Chiosis, Ari Melnick

Research output: Contribution to journalArticle

75 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4569-4582
Number of pages14
JournalJournal of Clinical Investigation
Volume120
Issue number12
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

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Lymphoma, Large B-Cell, Diffuse
B-Cell Lymphoma
Peptides
Histone Deacetylase Inhibitors
Therapeutics
Cell Line
HLA-B Antigens
Acetylation
Oncogenes
Transcriptome
Heterografts
Mutation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy. / Cerchietti, Leandro C.; Hatzi, Katerina; Caldas-Lopes, Eloisi; Yang, Shao Ning; Figueroa, Maria; Morin, Ryan D.; Hirst, Martin; Mendez, Lourdes; Shaknovich, Rita; Cole, Philip A.; Bhalla, Kapil; Gascoyne, Randy D.; Marra, Marco; Chiosis, Gabriela; Melnick, Ari.

In: Journal of Clinical Investigation, Vol. 120, No. 12, 01.12.2010, p. 4569-4582.

Research output: Contribution to journalArticle

Cerchietti, LC, Hatzi, K, Caldas-Lopes, E, Yang, SN, Figueroa, M, Morin, RD, Hirst, M, Mendez, L, Shaknovich, R, Cole, PA, Bhalla, K, Gascoyne, RD, Marra, M, Chiosis, G & Melnick, A 2010, 'BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy', Journal of Clinical Investigation, vol. 120, no. 12, pp. 4569-4582. https://doi.org/10.1172/JCI42869
Cerchietti, Leandro C. ; Hatzi, Katerina ; Caldas-Lopes, Eloisi ; Yang, Shao Ning ; Figueroa, Maria ; Morin, Ryan D. ; Hirst, Martin ; Mendez, Lourdes ; Shaknovich, Rita ; Cole, Philip A. ; Bhalla, Kapil ; Gascoyne, Randy D. ; Marra, Marco ; Chiosis, Gabriela ; Melnick, Ari. / BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 12. pp. 4569-4582.
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T1 - BCL6 repression of EP300 in human diffuse large B cell lymphoma cells provides a basis for rational combinatorial therapy

AU - Cerchietti, Leandro C.

AU - Hatzi, Katerina

AU - Caldas-Lopes, Eloisi

AU - Yang, Shao Ning

AU - Figueroa, Maria

AU - Morin, Ryan D.

AU - Hirst, Martin

AU - Mendez, Lourdes

AU - Shaknovich, Rita

AU - Cole, Philip A.

AU - Bhalla, Kapil

AU - Gascoyne, Randy D.

AU - Marra, Marco

AU - Chiosis, Gabriela

AU - Melnick, Ari

PY - 2010/12/1

Y1 - 2010/12/1

N2 - 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.

AB - 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.

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