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james bradner

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https://www.readbyqxmd.com/read/28275007/gene-expression-profiling-of-patient-derived-pancreatic-cancer-xenografts-predicts-sensitivity-to-the-bet-bromodomain-inhibitor-jq1-implications-for-individualized-medicine-efforts
#1
Benjamin Bian, Martin Bigonnet, Odile Gayet, Celine Loncle, Aurélie Maignan, Marine Gilabert, Vincent Moutardier, Stephane Garcia, Olivier Turrini, Jean-Robert Delpero, Marc Giovannini, Philippe Grandval, Mohamed Gasmi, Mehdi Ouaissi, Veronique Secq, Flora Poizat, Rémy Nicolle, Yuna Blum, Laetitia Marisa, Marion Rubis, Jean-Luc Raoul, James E Bradner, Jun Qi, Gwen Lomberk, Raul Urrutia, Andres Saul, Nelson Dusetti, Juan Iovanna
c-MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup...
March 8, 2017: EMBO Molecular Medicine
https://www.readbyqxmd.com/read/28249162/bet-bromodomain-inhibitors-engage-the-host-immune-system-and-regulate-expression-of-the-immune-checkpoint-ligand-pd-l1
#2
Simon J Hogg, Stephin J Vervoort, Sumit Deswal, Christopher J Ott, Jason Li, Leonie A Cluse, Paul A Beavis, Phillip K Darcy, Benjamin P Martin, Andrew Spencer, Anna K Traunbauer, Irina Sadovnik, Karin Bauer, Peter Valent, James E Bradner, Johannes Zuber, Jake Shortt, Ricky W Johnstone
BET 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...
February 28, 2017: Cell Reports
https://www.readbyqxmd.com/read/28241141/enl-links-histone-acetylation-to-oncogenic-gene-expression-in-acute-myeloid-leukaemia
#3
Liling Wan, Hong Wen, Yuanyuan Li, Jie Lyu, Yuanxin Xi, Takayuki Hoshii, Julia K Joseph, Xiaolu Wang, Yong-Hwee E Loh, Michael A Erb, Amanda L Souza, James E Bradner, Li Shen, Wei Li, Haitao Li, C David Allis, Scott A Armstrong, Xiaobing Shi
Cancer cells are characterized by aberrant epigenetic landscapes and often exploit chromatin machinery to activate oncogenic gene expression programs. Recognition of modified histones by 'reader' proteins constitutes a key mechanism underlying these processes; therefore, targeting such pathways holds clinical promise, as exemplified by the development of bromodomain and extra-terminal (BET) inhibitors. We recently identified the YEATS domain as an acetyl-lysine-binding module, but its functional importance in human cancer remains unknown...
March 9, 2017: Nature
https://www.readbyqxmd.com/read/28241139/transcription-control-by-the-enl-yeats-domain-in-acute-leukaemia
#4
Michael A Erb, Thomas G Scott, Bin E Li, Huafeng Xie, Joshiawa Paulk, Hyuk-Soo Seo, Amanda Souza, Justin M Roberts, Shiva Dastjerdi, Dennis L Buckley, Neville E Sanjana, Ophir Shalem, Behnam Nabet, Rhamy Zeid, Nana K Offei-Addo, Sirano Dhe-Paganon, Feng Zhang, Stuart H Orkin, Georg E Winter, James E Bradner
Recurrent chromosomal translocations producing a chimaeric MLL oncogene give rise to a highly aggressive acute leukaemia associated with poor clinical outcome. The preferential involvement of chromatin-associated factors as MLL fusion partners belies a dependency on transcription control. Despite recent progress made in targeting chromatin regulators in cancer, available therapies for this well-characterized disease remain inadequate, prompting the need to identify new targets for therapeutic intervention. Here, using unbiased CRISPR-Cas9 technology to perform a genome-scale loss-of-function screen in an MLL-AF4-positive acute leukaemia cell line, we identify ENL as an unrecognized gene that is specifically required for proliferation in vitro and in vivo...
March 9, 2017: Nature
https://www.readbyqxmd.com/read/28228643/a-chemical-probe-toolbox-for-dissecting-the-cancer-epigenome
#5
REVIEW
Jake Shortt, Christopher J Ott, Ricky W Johnstone, James E Bradner
Cancer cell hallmarks are underpinned by transcriptional programmes operating in the context of a dynamic and complicit epigenomic environment. Somatic alterations of chromatin modifiers are among the most prevalent cancer perturbations. There is a pressing need for targeted chemical probes to dissect these complex, interconnected gene regulatory circuits. Validated chemical probes empower mechanistic research while providing the pharmacological proof of concept that is required to translate drug-like derivatives into therapy for cancer patients...
February 23, 2017: Nature Reviews. Cancer
https://www.readbyqxmd.com/read/28187285/transcriptional-addiction-in-cancer
#6
REVIEW
James E Bradner, Denes Hnisz, Richard A Young
Cancer arises from genetic alterations that invariably lead to dysregulated transcriptional programs. These dysregulated programs can cause cancer cells to become highly dependent on certain regulators of gene expression. Here, we discuss how transcriptional control is disrupted by genetic alterations in cancer cells, why transcriptional dependencies can develop as a consequence of dysregulated programs, and how these dependencies provide opportunities for novel therapeutic interventions in cancer.
February 9, 2017: Cell
https://www.readbyqxmd.com/read/28169291/hotspots-of-aberrant-enhancer-activity-punctuate-the-colorectal-cancer-epigenome
#7
Andrea J Cohen, Alina Saiakhova, Olivia Corradin, Jennifer M Luppino, Katreya Lovrenert, Cynthia F Bartels, James J Morrow, Stephen C Mack, Gursimran Dhillon, Lydia Beard, Lois Myeroff, Matthew F Kalady, Joseph Willis, James E Bradner, Ruth A Keri, Nathan A Berger, Shondra M Pruett-Miller, Sanford D Markowitz, Peter C Scacheri
In addition to mutations in genes, aberrant enhancer element activity at non-coding regions of the genome is a key driver of tumorigenesis. Here, we perform epigenomic enhancer profiling of a cohort of more than forty genetically diverse human colorectal cancer (CRC) specimens. Using normal colonic crypt epithelium as a comparator, we identify enhancers with recurrently gained or lost activity across CRC specimens. Of the enhancers highly recurrently activated in CRC, most are constituents of super enhancers, are occupied by AP-1 and cohesin complex members, and originate from primed chromatin...
February 7, 2017: Nature Communications
https://www.readbyqxmd.com/read/28024402/relative-binding-free-energy-calculations-applied-to-protein-homology-models
#8
Daniel Cappel, Michelle Lynn Hall, Eelke B Lenselink, Thijs Beuming, Jun Qi, James Bradner, Woody Sherman
A significant challenge and potential high-value application of computer-aided drug design is the accurate prediction of protein-ligand binding affinities. Free energy perturbation (FEP) using molecular dynamics (MD) sampling is among the most suitable approaches to achieve accurate binding free energy predictions, due to the rigorous statistical framework of the methodology, correct representation of the energetics, and thorough treatment of the important degrees of freedom in the system (including explicit waters)...
December 27, 2016: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/27862999/assessment-of-bromodomain-target-engagement-by-a-series-of-bi2536-analogues-with-miniaturized-bet-bret
#9
Luke W Koblan, Dennis L Buckley, Christopher J Ott, Mark E Fitzgerald, Stuart W J Ember, Jin-Yi Zhu, Shuai Liu, Justin M Roberts, David Remillard, Sarah Vittori, Wei Zhang, Ernst Schonbrunn, James E Bradner
Evaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain- and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536...
December 6, 2016: ChemMedChem
https://www.readbyqxmd.com/read/27803105/bet-inhibitors-suppress-aldh-activity-by-targeting-aldh1a1-super-enhancer-in-ovarian-cancer
#10
Yuhki Yokoyama, Hengrui Zhu, Jeong Heon Lee, Andrew V Kossenkov, Sherry Y Wu, Jayamanna M Wickramasinghe, Xiangfan Yin, Katherine C Palozola, Alessandro Gardini, Louise C Showe, Kenneth S Zaret, Qin Liu, David Speicher, Jose R Conejo-Garcia, James E Bradner, Zhiguo Zhang, Anil K Sood, Tamas Ordog, Benjamin G Bitler, Rugang Zhang
The emergence of tumor cells with certain stem-like characteristics, such as high aldehyde dehydrogenase (ALDH) activity due to ALDH1A1 expression, contributes to chemotherapy resistance and tumor relapse. However, clinically applicable inhibitors of ALDH activity have not been reported. There is evidence to suggest that epigenetic regulation of stem-related genes contributes to chemotherapy efficacy. Here, we show that bromodomain and extraterminal (BET) inhibitors suppress ALDH activity by abrogating BRD4-mediated ALDH1A1 expression through a super-enhancer element and its associated enhancer RNA...
November 1, 2016: Cancer Research
https://www.readbyqxmd.com/read/27799547/discovery-of-selective-small-molecule-hdac6-inhibitor-for-overcoming-proteasome-inhibitor-resistance-in-multiple-myeloma
#11
Teru Hideshima, Jun Qi, Ronald M Paranal, Weiping Tang, Edward Greenberg, Nathan West, Meaghan E Colling, Guillermina Estiu, Ralph Mazitschek, Jennifer A Perry, Hiroto Ohguchi, Francesca Cottini, Naoya Mimura, Güllü Görgün, Yu-Tzu Tai, Paul G Richardson, Ruben D Carrasco, Olaf Wiest, Stuart L Schreiber, Kenneth C Anderson, James E Bradner
Multiple myeloma (MM) has proven clinically susceptible to modulation of pathways of protein homeostasis. Blockade of proteasomal degradation of polyubiquitinated misfolded proteins by the proteasome inhibitor bortezomib (BTZ) achieves responses and prolongs survival in MM, but long-term treatment with BTZ leads to drug-resistant relapse in most patients. In a proof-of-concept study, we previously demonstrated that blocking aggresomal breakdown of polyubiquitinated misfolded proteins with the histone deacetylase 6 (HDAC6) inhibitor tubacin enhances BTZ-induced cytotoxicity in MM cells in vitro...
November 15, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27775715/design-and-characterization-of-bivalent-bet-inhibitors
#12
Minoru Tanaka, Justin M Roberts, Hyuk-Soo Seo, Amanda Souza, Joshiawa Paulk, Thomas G Scott, Stephen L DeAngelo, Sirano Dhe-Paganon, James E Bradner
Cellular signaling is often propagated by multivalent interactions. Multivalency creates avidity, allowing stable biophysical recognition. Multivalency is an attractive strategy for achieving potent binding to protein targets, as the affinity of bivalent ligands is often greater than the sum of monovalent affinities. The bromodomain and extraterminal domain (BET) family of transcriptional coactivators features tandem bromodomains through which BET proteins bind acetylated histones and transcription factors...
December 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27774131/development-of-a-potent-and-selective-hdac8-inhibitor
#13
Oscar J Ingham, Ronald M Paranal, William B Smith, Randolph A Escobar, Han Yueh, Tracy Snyder, John A Porco, James E Bradner, Aaron B Beeler
A novel, isoform-selective inhibitor of histone deacetylase 8 (HDAC8) has been discovered by the repurposing of a diverse compound collection. Medicinal chemistry optimization led to the identification of a highly potent (0.8 nM) and selective inhibitor of HDAC8.
October 13, 2016: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/27669656/inhibition-of-bet-proteins-and-epigenetic-signaling-as-a-potential-treatment-for-osteoporosis
#14
Marc Baud'huin, François Lamoureux, Camille Jacques, Lidia Rodriguez Calleja, Thibaut Quillard, Céline Charrier, Jérome Amiaud, Martine Berreur, Bénédicte Brounais-LeRoyer, Robert Owen, Gwendolen C Reilly, James E Bradner, Dominique Heymann, Benjamin Ory
Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro...
January 2017: Bone
https://www.readbyqxmd.com/read/27650498/bromodomain-and-extraterminal-protein-inhibition-blocks-growth-of-triple-negative-breast-cancers-through-the-suppression-of-aurora-kinases
#15
Jennifer M Sahni, Sylvia S Gayle, Kristen L Weber Bonk, Leslie Cuellar Vite, Jennifer L Yori, Bryan Webb, Erika K Ramos, Darcie D Seachrist, Melissa D Landis, Jenny C Chang, James E Bradner, Ruth A Keri
Bromodomain and extraterminal (BET) proteins are epigenetic "readers" that recognize acetylated histones and mark areas of the genome for transcription. BRD4, a BET family member protein, has been implicated in a number of types of cancer, and BET protein inhibitors (BETi) are efficacious in many preclinical cancer models. However, the drivers of response to BETi vary depending on tumor type, and little is known regarding the target genes conveying BETi activity in triple-negative breast cancer (TNBC). Here, we show that BETi repress growth of multiple in vitro and in vivo models of TNBC by inducing two terminal responses: apoptosis and senescence...
November 4, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27630126/chronic-myelogenous-leukemia-initiating-cells-require-polycomb-group-protein-ezh2
#16
Huafeng Xie, Cong Peng, Jialiang Huang, Bin E Li, Woojin Kim, Elenoe C Smith, Yuko Fujiwara, Jun Qi, Giulia Cheloni, Partha P Das, Minh Nguyen, Shaoguang Li, James E Bradner, Stuart H Orkin
Tyrosine kinase inhibitors (TKI) have revolutionized chronic myelogenous leukemia (CML) management. Disease eradication, however, is hampered by innate resistance of leukemia-initiating cells (LIC) to TKI-induced killing, which also provides the basis for subsequent emergence of TKI-resistant mutants. We report that EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), is overexpressed in CML LICs and required for colony formation and survival and cell-cycle progression of CML cell lines. A critical role for EZH2 is supported by genetic studies in a mouse CML model...
November 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27626654/bet-bromodomain-inhibition-promotes-anti-tumor-immunity-by-suppressing-pd-l1-expression
#17
Hengrui Zhu, Fee Bengsch, Nikolaos Svoronos, Melanie R Rutkowski, Benjamin G Bitler, Michael J Allegrezza, Yuhki Yokoyama, Andrew V Kossenkov, James E Bradner, Jose R Conejo-Garcia, Rugang Zhang
Restoration of anti-tumor immunity by blocking PD-L1 signaling through the use of antibodies has proven to be beneficial in cancer therapy. Here, we show that BET bromodomain inhibition suppresses PD-L1 expression and limits tumor progression in ovarian cancer. CD274 (encoding PD-L1) is a direct target of BRD4-mediated gene transcription. In mouse models, treatment with the BET inhibitor JQ1 significantly reduced PD-L1 expression on tumor cells and tumor-associated dendritic cells and macrophages, which correlated with an increase in the activity of anti-tumor cytotoxic T cells...
September 13, 2016: Cell Reports
https://www.readbyqxmd.com/read/27612420/atad2-is-an-epigenetic-reader-of-newly-synthesized-histone-marks-during-dna-replication
#18
Seong Joo Koo, Amaury E Fernández-Montalván, Volker Badock, Christopher J Ott, Simon J Holton, Oliver von Ahsen, Joern Toedling, Sarah Vittori, James E Bradner, Mátyás Gorjánácz
ATAD2 (ATPase family AAA domain-containing protein 2) is a chromatin regulator harboring an AAA+ ATPase domain and a bromodomain, previously proposed to function as an oncogenic transcription co-factor. Here we suggest that ATAD2 is also required for DNA replication. ATAD2 is co-expressed with genes involved in DNA replication in various cancer types and predominantly expressed in S phase cells where it localized on nascent chromatin (replication sites). Our extensive biochemical and cellular analyses revealed that ATAD2 is recruited to replication sites through a direct interaction with di-acetylated histone H4 at K5 and K12, indicative of newly synthesized histones during replication-coupled chromatin reassembly...
October 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27590350/multi-focal-control-of-mitochondrial-gene-expression-by-oncogenic-myc-provides-potential-therapeutic-targets-in-cancer
#19
Amanda R Oran, Clare M Adams, Xiao-Yong Zhang, Victoria J Gennaro, Harla K Pfeiffer, Hestia S Mellert, Hans E Seidel, Kirsten Mascioli, Jordan Kaplan, Mahmoud R Gaballa, Chen Shen, Isidore Rigoutsos, Michael P King, Justin L Cotney, Jamie J Arnold, Suresh D Sharma, Ubaldo E Martinez-Outschoorn, Christopher R Vakoc, Lewis A Chodosh, James E Thompson, James E Bradner, Craig E Cameron, Gerald S Shadel, Christine M Eischen, Steven B McMahon
Despite ubiquitous activation in human cancer, essential downstream effector pathways of the MYC transcription factor have been difficult to define and target. Using a structure/function-based approach, we identified the mitochondrial RNA polymerase (POLRMT) locus as a critical downstream target of MYC. The multifunctional POLRMT enzyme controls mitochondrial gene expression, a process required both for mitochondrial function and mitochondrial biogenesis. We further demonstrate that inhibition of this newly defined MYC effector pathway causes robust and selective tumor cell apoptosis, via an acute, checkpoint-like mechanism linked to aberrant electron transport chain complex assembly and mitochondrial reactive oxygen species (ROS) production...
November 8, 2016: Oncotarget
https://www.readbyqxmd.com/read/27535106/targeting-chromatin-regulators-inhibits-leukemogenic-gene-expression-in-npm1-mutant-leukemia
#20
Michael W M Kühn, Evelyn Song, Zhaohui Feng, Amit Sinha, Chun-Wei Chen, Aniruddha J Deshpande, Monica Cusan, Noushin Farnoud, Annalisa Mupo, Carolyn Grove, Richard Koche, James E Bradner, Elisa de Stanchina, George S Vassiliou, Takayuki Hoshii, Scott A Armstrong
Homeobox (HOX) proteins and the receptor tyrosine kinase FLT3 are frequently highly expressed and mutated in acute myeloid leukemia (AML). Aberrant HOX expression is found in nearly all AMLs that harbor a mutation in the Nucleophosmin (NPM1) gene, and FLT3 is concomitantly mutated in approximately 60% of these cases. Little is known about how mutant NPM1 (NPM1(mut)) cells maintain aberrant gene expression. Here, we demonstrate that the histone modifiers MLL1 and DOT1L control HOX and FLT3 expression and differentiation in NPM1(mut) AML...
October 2016: Cancer Discovery
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