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BCL6 repression of EP300 provides a basis for rational combinatorial therapy in diffuse large B cell lymphomas.

ABSTRACT: The BCL6 transcriptional repressor is a critical oncogene in diffuse large B-cell lymphomas (DLBCL). The specific BCL6 inhibitor RI-BPI potently kills DLBCL cells. We find that RI-BPI induces a particular gene expression signature in DLBCL. In order to identify classes of drugs that might synergize with RIBPI we examined the connectivity of this signature and found a strong association with HDAC and Hsp90 inhibitors. This was explained by the discovery that BCL6 directly represses the p300 lysine acetyltransferase and its co-factor BAT3. RI-BPI induced expression of p300 and BAT3, and p300 acetyltransferase activity, resulting in acetylation of p300 targets like p53 and Hsp90. As a consequence, RI-BPI could attenuate Hsp90 chaperone function, similar to the effect of Hsp90 and HDAC inhibitors. Induction of p300 and BAT3 was required for the anti-lymphoma effects of RI-BPI since specific blockade of either protein rescued DLBCL cells from the BCL6 inhibitor. RI-BPI synergistically killed DLBCL cells in combination with HDAC inhibitors (SAHA, TSA and VPA) and Hsp90 inhibitors (17-DMAG and PUH71). The combination of RI-BPI and SAHA, or RI-BPI and PU-H71 potently suppressed or even eradicated human DLBCL in mice. BCL6 repression of EP300 thus provides a basis for rational targeted combinatorial therapy for patients with DLBCL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE24236 | GEO | 2010/09/21

SECONDARY ACCESSION(S): PRJNA132935

REPOSITORIES: GEO

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Project description:Aggressive double and triple hit (DH/TH) DLBCL feature activation of Hsp90 stress pathways. Herein, we show that Hsp90 controls post-transcriptional dynamics of key mRNA species including those encoding BCL6, MYC and BCL2. Using a proteomics approach, we found that Hsp90 binds to and maintains activity of eIF4E (eukaryotic translation initiation factor 4E). EIF4E drives nuclear export and translation of BCL6, MYC and BCL2 mRNA. eIF4E RIP-sequencing in DLBCL suggests that nuclear eIF4E controls an extended program that includes BCR signaling, cellular metabolism and epigenetic regulation. Accordingly, eIF4E was required for survival of DLBCL including the most aggressive subtypes DH/TH lymphomas. Indeed, eIF4E inhibition induces tumor regression in cell line and patient-derived tumorgrafts of TH-DLBCL, even in the presence of elevated Hsp90 activity. Targeting Hsp90 is typically limited by counter-regulatory elevation of Hsp70B, which induces resistance to Hsp90 inhibitors. Surprisingly, we identify Hsp70 mRNA as an eIF4E target. In this way, eIF4E inhibition can overcome drug resistance to Hsp90 inhibitors. Accordingly, rational combinatorial inhibition of eIF4E and Hsp90 inhibitors resulted in cooperative anti-lymphoma activity in DH/TH DLBCL in vitro and in vivo. We found that eIF4E activity regulates the nuclear export of BCL6, MYC, and BCL2 in DH/TH DLBCLs. To determine the extent of nuclear eIF4E activity in DH/TH DLBCLs and how these programs can support the oncogenic activity of BCL6, MYC and/or BCL2 transcripts, we conducted eIF4E-RIP of nuclear RNA followed by RNA-sequencing in OCI-Ly1 cells in triplicates. To understand the changes in gene expression after ribavarin in a clinically relevant sample, we generated a patient-derived xenograft (PDX) in NSG mice from a de-identified specimen isolated from a patient prior to treatment harboring a triple-hit ABC-type DLBCL. PDX cells from passage four (PDX-4) were implanted into NSG mice. When tumors were palpable, mice were randomized to receive vehicle or 80 mg/kg/b.i.d. ribavarin intraperitoneally for 10 days. We isolated RNA from tumors treated with vehicle (n=2) or ribavarin (n=2) and performed mRNA-seq.

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BCL6 repression of EP300 provides a basis for rational combinatorial therapy in diffuse large B cell lymphomas.

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