BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members

Hogg, Simon J.; Newbold, Andrea; Vervoort, Stephin J.; Cluse, Leonie A.; Martin, Benjamin P.; Gregory, Gareth P.; Lefebure, Marcus; Vidacs, Eva; Tothill, Richard W.; Bradner, James E.; Shortt, Jake; Johnstone, Ricky W.

doi:10.1158/1535-7163.mct-15-0924

Cited by 61 publications

(58 citation statements)

References 43 publications

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“…4-sU labeling analysis demonstrated a significant decrease in nascent Cd274 mRNA following exposure of Eμ- Myc lymphomas to JQ1 while Actb (beta-actin) mRNA levels remained unchanged (Figure 3A). We recently demonstrated that the Eμ- Myc transgene was resistant to the effects of JQ1 that can only downregulate the expression of low levels of endogenous Myc in these lymphomas (Hogg et al., 2016). Similar differential effects of JQ1 on transgenic versus endogenous Myc were demonstrated by 4-sU labeling (Figure 3A), indicating high levels of transgenic Myc are maintained despite BET inhibition.…”

Section: Resultsmentioning

confidence: 99%

“…While deregulation of MYC has been the focus of much attention when assessing the mechanisms-of-action of BETi, other genes important for the proliferation and/or survival of tumor cells such as BCL2 and CDK6 are also affected by BETi treatment (Dawson et al., 2011). Indeed, we have demonstrated that the BETi JQ1 can kill Eμ- Myc lymphoma cells via modulation of BCL-2 family proteins without affecting the levels of transgenic Myc (Hogg et al., 2016). …”

Section: Introductionmentioning

confidence: 99%

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BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1

et al. 2017

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SummaryBET inhibitors (BETi) target bromodomain-containing proteins and are currently being evaluated as anti-cancer agents. We find that maximal therapeutic effects of BETi in a Myc-driven B cell lymphoma model required an intact host immune system. Genome-wide analysis of the BETi-induced transcriptional response identified the immune checkpoint ligand Cd274 (Pd-l1) as a Myc-independent, BETi target-gene. BETi directly repressed constitutively expressed and interferon-gamma (IFN-γ) induced CD274 expression across different human and mouse tumor cell lines and primary patient samples. Mechanistically, BETi decreased Brd4 occupancy at the Cd274 locus without any change in Myc occupancy, resulting in transcriptional pausing and rapid loss of Cd274 mRNA production. Finally, targeted inhibition of the PD-1/PD-L1 axis by combining anti-PD-1 antibodies and the BETi JQ1 caused synergistic responses in mice bearing Myc-driven lymphomas. Our data uncover an interaction between BETi and the PD-1/PD-L1 immune-checkpoint and provide mechanistic insight into the transcriptional regulation of CD274.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1

et al. 2017

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“…In the present study, sensitivity to JQ1 was determined by apoptosis and occurred in a MYC‐independent way. Recent studies have also shown that BET inhibitors induce apoptosis in cancer cells independently of MYC . BET inhibition upregulates gene expression of the pro‐apoptotic protein BIM and activates the apoptotic pathway in several malignancies .…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have also shown that BET inhibitors induce apoptosis in cancer cells independently of MYC. [46][47][48][49] BET inhibition upregulates gene expression of the pro-apoptotic protein BIM and activates the apoptotic pathway in several malignancies. 50,51 These findings were consistent with our data that JQ1 upregulated the expression of BIM and BAX in RBE cells through enrichment of the transcriptionally active histone mark H3K4me3 at the promoter region of the genes (Figure 3D-F).…”

Section: Icc Cellsmentioning

confidence: 99%

Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1

et al. 2018

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Cholangiocarcinoma is a life‐threatening disease with a poor prognosis. Although genome analysis unraveled some genetic mutation profiles in cholangiocarcinoma, it remains unknown whether such genetic abnormalities relate to the effects of anticancer drugs. Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) are exclusively found in almost 20% of intrahepatic cholangiocarcinoma (ICC). Recently, the anticancer effects of BET inhibitors including JQ1 have been shown in various tumors. In the present study, we report that the antigrowth effect of JQ1 differs among ICC cells and IDH1 mutation sensitizes ICC cells to JQ1. RBE cells harboring IDH1 mutation was more sensitive to JQ1 than HuCCT1 or HuH28 cells with wild‐type IDH1. JQ1 induced apoptosis only in RBE cells through the upregulation of proapoptotic genes BAX and BIM. We found that the antigrowth effect was not attributed to downregulation of the MYC gene as a well‐known target of JQ1 in various cancer cells. Notably, the forced expression of mutant IDH1 successfully sensitized HuCCT1 cells to JQ1. In addition, AGI‐5198, a selective inhibitor of mutant IDH1 partially reversed the decrease in viability after JQ1 treatment and also suppressed the JQ1‐induced apoptosis in RBE cells. These data suggest that IDH1 mutation contributed to the growth inhibitory effect of JQ1 in RBE cells. Furthermore, given that the effect of mutant IDH1 was not recapitulated in glioblastoma cells, the enhancement of JQ1 sensitivity by IDH1 mutation seems to be specific for ICC cells. Our findings propose a new stratified therapeutic strategy based on IDH1 mutation in ICC.

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“…More recently, bromodomain and extraterminal (BET) inhibitors have been shown to effectively suppress MYC transcription in various types of cancer cells and inhibit tumor growth in animal models (27), which has led to the development of drug candidates currently in clinical trials. However, the selectivity of these epigenetic-based approaches for targeting MYC transcription is not yet fully established; indeed, in some cancers, the anticancer activity of BET inhibitors has been attributed to their inhibition of genes other than MYC (28)(29)(30).…”

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confidence: 99%

Small molecule selectively suppresses MYC transcription in cancer cells

Bouvard

Lim

Ludka

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Stauprimide is a staurosporine analog that promotes embryonic stem cell (ESC) differentiation by inhibiting nuclear localization of the MYC transcription factor NME2, which in turn results in downregulation of MYC transcription. Given the critical role the oncogene MYC plays in tumor initiation and maintenance, we explored the potential of stauprimide as an anticancer agent. Here we report that stauprimide suppresses MYC transcription in cancer cell lines derived from distinct tissues. Using renal cancer cells, we confirmed that stauprimide inhibits NME2 nuclear localization. Gene expression analysis also confirmed the selective down-regulation of MYC target genes by stauprimide. Consistent with this activity, administration of stauprimide inhibited tumor growth in rodent xenograft models. Our study provides a unique strategy for selectively targeting MYC transcription by pharmacological means as a potential treatment for MYCdependent tumors.MYC | stauprimide | NME2 | nuclear localization | cancer T he transcription factor MYC participates in diverse cellular processes by regulating the transcription of a large number of genes involved in gene expression, cell division, apoptosis, cell adhesion, stem cell self-renewal and differentiation, and metabolism (1-3). MYC is an oncogene whose expression is elevated in up to 75% of all cancers with various tissue origins (4); MYC expression levels also correlate with prognostic outcomes in patients of various types of malignancies (5, 6). In addition to its well-established roles in tumor initiation and cancer cell survival and proliferation, MYC has been shown to be involved in tumor microenvironment remodeling, drug resistance, and cancer stem cell maintenance (7-9). Recent studies have also revealed a role for MYC in regulating the transcription of immune checkpoint genes, including CD47 and PD-L1 in cancer cells, suggesting that MYC is involved in cancer escape from immune surveillance (10).Overexpression of MYC is able to induce malignant transformation in skin (11), lung (12), liver (13), breast (14, 15), and hematopoietic cells (16) in transgenic mouse models, and termination of MYC overexpression results in halted cancer cell proliferation, increased apoptosis and terminal differentiation, and tumor regression. Furthermore, inhibition of endogenous MYC by the inducible expression of a dominant-negative variant of MYC, Omomyc, is able to induce tumor regression in transgenic mouse models of lung cancer (17). More intriguingly, transient deactivation of MYC overexpression (18) and episodic expression of Omomyc (19) have been shown to induce irreversible tumor regression in osteosarcoma and lung cancer transgenic mouse models, suggesting the potential of MYCtargeted anticancer therapies.Drug discovery efforts have attempted to directly and indirectly modulate MYC-dependent transcription. For example, compounds have been identified that disrupt the interaction between MYC and its transcriptional partner MAX to suppress downstream gene transcription (20)(21)(22)(23)(2...

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BET Inhibition Induces Apoptosis in Aggressive B-Cell Lymphoma via Epigenetic Regulation of BCL-2 Family Members

Cited by 61 publications

References 43 publications

BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1

BET-Bromodomain Inhibitors Engage the Host Immune System and Regulate Expression of the Immune Checkpoint Ligand PD-L1

Isocitrate dehydrogenase 1 mutation sensitizes intrahepatic cholangiocarcinoma to the BET inhibitor JQ1

Small molecule selectively suppresses MYC transcription in cancer cells

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