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

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.

Mechanisms of epigenetic deregulation in lymphoid neoplasms

“…[54][55][56]82 In addition, focal deletion and mutations involving CREBBP were found in 18% of relapsed ALL. 57 Mutations in CREBBP and EP300 are often heterozygous and may disrupt their acetyltransferase activity, affecting the cellular acetylome and promoting the oncogenic phenotype.…”

“…Indeed, mutations affecting the HAT activity of CREBBP and EP300 promote the activation of BCL6 and HSP90 while destabilizing P53. 56,82 Therefore, loss of BCL6 acetylation in CREBBP HAT or EP300 HAT mutant cells may exacerbate the oncogenic activity of BCL6 and HSP90 in these lymphomas. Although the balance between HAT and HDACs can be pharmacologically manipulated by using HDAC inhibitors (HDACi), DLBCL with CREBBP HAT and/or EP300 HAT mutations tend to be resistant to this strategy.…”

“…Although the balance between HAT and HDACs can be pharmacologically manipulated by using HDAC inhibitors (HDACi), DLBCL with CREBBP HAT and/or EP300 HAT mutations tend to be resistant to this strategy. 82 The combination of HDACi with molecules that inactivate EP300 substrate proteins such as HSP90 and BCL6 may offer a way to circumvent this problem. 82 Interestingly, BCL6 itself can repress EP300 in DLBCLs, and treatment with RI-BPI, a BCL6 peptide inhibitor, can induce EP300 expression, which is required for killing of DLBCL cells by RI-BPI, 82 providing an alternative way to restore the HAT/HDAC balance in lymphomas with wild-type enzymes.…”

“…82 The combination of HDACi with molecules that inactivate EP300 substrate proteins such as HSP90 and BCL6 may offer a way to circumvent this problem. 82 Interestingly, BCL6 itself can repress EP300 in DLBCLs, and treatment with RI-BPI, a BCL6 peptide inhibitor, can induce EP300 expression, which is required for killing of DLBCL cells by RI-BPI, 82 providing an alternative way to restore the HAT/HDAC balance in lymphomas with wild-type enzymes. Currently, it is important to establish a mechanistic link between CREBBP/EP300 mutations, aberrant histone acetylation, impaired target regulation, and lymphomagenesis to design a targeted therapy specific for lymphomas with CREBBP/EP300 mutations.…”

Perspectives and future directions for epigenetics in hematology

“…(Blood. 2013;121 (26): [5131][5132][5133][5134][5135][5136][5137] In this issue, we present the last of our series of reviews surveying epigenetics in hematology. We started with an overview of the foundations of epigenetics with respect to hematology and have explored the clinical relevance of epigenetics for each of the major classes of hematologic malignancies (Table 1 1-5 ).…”