The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML

Gerlach, Daniel; Tontsch-Grunt, Ulrike; Baum, Anke; Popow, Johannes; Scharn, Dirk; Hofmann, Marco H.; Engelhardt, Harald; Kaya, Onur; Beck, Janina; Schweifer, Norbert; Gerstberger, Thomas; Zuber, Johannes; Savarese, Fabio; Kraut, Norbert

doi:10.1038/s41388-018-0150-2

Cited by 69 publications

(58 citation statements)

References 62 publications

(80 reference statements)

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“…7b). Moreover, using published pCHiC data from human CD34+ cells 18 , we could also demonstrate that the interaction was also present across species, and ChIP-seq data from ourselves 34 and others 35,36 indicated that this region also contained a SE in human AML cells that overexpress HOXA genes (OCI-AML3 cell line) but not in AML cells that do not (Kasumi-1 cell line) ( Supplementary Fig. 7b).…”

Section: Integration Of Chromatin Alterations Dna Topology and Gene mentioning

confidence: 60%

“…A human genomic region homologous to mouse Hoxa-LRSE was identified using the LIFTOVER ChIP-seq in human CD34+ HSPCs 34,35 . Chromatin accessibility assessed by mapping DNase Hypersenstivity Site (DHS-seq) or ATAC-seq was shown in NPM1 mutant AML patients (two with FLT3-ITD and two without) or in human CD34+ HSPCs, respectively 37,38 .…”

Section: Evaluation Of Human Homologous Region To Mouse Hoxa-lrsementioning

confidence: 99%

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Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

Yun

Vohra

Mupo

et al. 2020

Preprint

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Altered transcription is a cardinal feature of acute myeloid leukemia (AML), however, exactly how mutations synergize to remodel the epigenetic landscape and rewire 3-Dimensional (3-D) DNA topology is unknown. Here we apply an integrated genomic approach to a murine allelic series that models the two most common mutations in AML, Flt3-ITD and Npm1c. We then deconvolute the contribution of each mutation to alterations of the epigenetic landscape and genome organization, and infer how mutations synergize in the induction of AML. These analyses allow the identification of long-range cis-regulatory circuits, including a novel superenhancer of the Hoxa locus, as well as larger and more detailed gene-regulatory networks, whose importance we demonstrate through perturbation of network members.

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Section: Integration Of Chromatin Alterations Dna Topology and Gene mentioning

confidence: 60%

Section: Evaluation Of Human Homologous Region To Mouse Hoxa-lrsementioning

confidence: 99%

Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

Yun

Vohra

Mupo

et al. 2020

Preprint

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“…The sensitivity of super-enhancers to transcriptional inhibitors is also being exploited as a therapeutic strategy in various tumor contexts. Super-enhancers often drive the high-level expression of oncogenes and super-enhancer inhibition by CDK7 and BET inhibitors can effectively block tumor cell proliferation and enhance survival in mouse models of disease (41-43). MiR-155 expression in human umbilical vein endothelial cells is sensitive to inhibition by BET and NF-κB inhibitors (44).…”

Section: Discussionmentioning

confidence: 99%

Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells

Wood

Carvell

Gunnell

et al. 2018

Preprint

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16The oncogenic microRNA-155 (miR-155) is the most frequently upregulated miRNA in 17 Epstein-Barr virus (EBV)-positive B cell malignancies and is upregulated in other non-18 viral lymphomas. Both the EBV nuclear antigen 2 (EBNA2), and B cell transcription 19 factor, interferon regulatory factor 4 (IRF4) are known to activate transcription of the host 20 cell gene from which miR-155 is processed (miR-155HG, BIC). EBNA2 also activates 21IRF4 transcription indicating that EBV may upregulate miR-155 through direct and 22 indirect mechanisms. The mechanism of transcriptional regulation of IRF4 and miR-23 155HG by EBNA2 however has not been defined. We demonstrate that EBNA2 can 24 activate IRF4 and miR-155HG expression through specific upstream enhancers that are 25 dependent on the Notch signaling transcription factor RBPJ, a known binding partner of 26 EBNA2. We demonstrate that in addition to activation of the miR-155HG promoter, IRF4 27 can also activate miR-155HG via the upstream enhancer also targeted by EBNA2. Gene 28 editing to remove the EBNA2-and IRF4-responsive miR-155HG enhancer located 60 kb 29 upstream of miR-155HG led to reduced miR155HG expression in EBV-infected cells. Our 30 data therefore demonstrate that specific RBPJ-dependent enhancers regulate the IRF4-31 miR-155 expression network and play a key role in the maintenance of miR-155 expression 32 in EBV-infected B cells. These findings provide important insights that will improve our 33 understanding of miR-155 control in B cell malignancies. 34 35 IMPORTANCE 36MicroRNA-155 (miR-155) is expressed at high level in many human cancers particularly 37 lymphomas. Epstein-Barr virus (EBV) infects human B cells and drives the development 38. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint (which . http://dx.doi.org/10.1101/311886 doi: bioRxiv preprint first posted online May. 1, 2018; 3 of numerous lymphomas. Two EBV-encoded genes (LMP1 and EBNA2) upregulate miR-39 155 expression and miR-155 expression is required for the growth of EBV-infected B cells. 40We show that the EBV transcription factor EBNA2 upregulates miR-155 expression by 41 activating an enhancer upstream from the miR-155 host gene (miR-155HG) from which 42 miR-155 is derived. We show that EBNA2 also indirectly activates miR-155 expression 43 through enhancer-mediated activation of IRF4. IRF4 then activates both the miR-155HG 44 promoter and the upstream enhancer, independently of EBNA2. Gene editing to remove 45 the miR-155HG enhancer leads to a reduction in miR-155HG expression. We therefore 46 identify enhancer-mediated activation of miR-155HG as a critical step in promoting B cell 47 growth and a likely driver of lymphoma development. 48 49. CC-BY 4.0 International license It is made available under a was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in pe...

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“…While BET inhibitors are being investigated as monotherapy, their use in combination with CDK9 inhibitors may show even more promising outcomes for treatment of AML. For example, BET inhibitor BI 894999 has shown activity in AML cell lines, primary patient samples, and xenograft models as a monotherapy and in combination with CDK9 inhibitors LDC000067 and alvocidib (186). Combined BET and CDK9 inhibition results in rapid induction of apoptosis in vivo and in cultured cells, perhaps due to a global arrest of transcriptional elongation (186).…”

Section: Combination Therapy Utilizing Cdk9 Inhibitionmentioning

confidence: 99%

“…For example, BET inhibitor BI 894999 has shown activity in AML cell lines, primary patient samples, and xenograft models as a monotherapy and in combination with CDK9 inhibitors LDC000067 and alvocidib (186). Combined BET and CDK9 inhibition results in rapid induction of apoptosis in vivo and in cultured cells, perhaps due to a global arrest of transcriptional elongation (186). A phase 1 dose-finding clinical study of BI 894999 monotherapy in solid tumors has been initiated (NCT02516553).…”

Section: Combination Therapy Utilizing Cdk9 Inhibitionmentioning

confidence: 99%

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

Tibes

Bogenberger

2019

Front. Oncol.

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Acute myeloid leukemia (AML) is the most common adult acute leukemia. Survival remains poor, despite decades of scientific advances. Cytotoxic induction chemotherapy regimens are standard-of-care for most patients. Many investigations have highlighted the genomic heterogeneity of AML, and several new targeted therapeutic options have recently been approved. Additional novel therapies are showing promising clinical results and may rapidly transform the therapeutic landscape of AML. Despite the emerging clinical success of B-cell lymphoma (BCL)-2 targeting in AML and a large body of preclinical data supporting myeloid leukemia cell (MCL)-1 as an attractive therapeutic target for AML, MCL-1 targeting remains relatively unexplored, although novel MCL-1 inhibitors are under clinical investigation. Inhibitors of cyclin-dependent kinases (CDKs) involved in the regulation of transcription, CDK9 in particular, are being investigated in AML as a strategy to target MCL-1 indirectly. In this article, we review the basis for CDK inhibition in oncology with a focus on relevant preclinical mechanism-of-action studies of CDK9 inhibitors in the context of their therapeutic potential specifically in AML.

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The novel BET bromodomain inhibitor BI 894999 represses super-enhancer-associated transcription and synergizes with CDK9 inhibition in AML

Cited by 69 publications

References 62 publications

Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

Mutational synergy coordinately remodels chromatin accessibility, enhancer landscape and 3-Dimensional DNA topology to alter gene expression during leukemia induction

Enhancer control of miR-155 expression in Epstein-Barr virus infected B cells

Transcriptional Silencing of MCL-1 Through Cyclin-Dependent Kinase Inhibition in Acute Myeloid Leukemia

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