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JOURNAL ARTICLE
Catríona M Dowling, Kate E R Hollinshead, Alessandra Di Grande, Justin Pritchard, Hua Zhang, Eugene T Dillon, Kathryn Haley, Eleni Papadopoulos, Anita K Mehta, Rachel Bleach, Andreas U Lindner, Brian Mooney, Heiko Düssmann, Darran O'Connor, Jochen H M Prehn, Kieran Wynne, Michael Hemann, James E Bradner, Alec C Kimmelman, Jennifer L Guerriero, Gerard Cagney, Kwok-Kin Wong, Anthony G Letai, Tríona Ní Chonghaile
Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a "hit" compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC)...
January 2021: Science Advances
#22
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
No abstract text is available yet for this article.
July 3, 2020: Journal of Biological Chemistry
#23
JOURNAL ARTICLE
Ryosuke Shirasaki, Geoffrey M Matthews, Sara Gandolfi, Ricardo de Matos Simoes, Dennis L Buckley, Joseline Raja Vora, Quinlan L Sievers, Johanna B Brüggenthies, Olga Dashevsky, Haley Poarch, Huihui Tang, Megan A Bariteau, Michal Sheffer, Yiguo Hu, Sondra L Downey-Kopyscinski, Paul J Hengeveld, Brian J Glassner, Eugen Dhimolea, Christopher J Ott, Tinghu Zhang, Nicholas P Kwiatkowski, Jacob P Laubach, Robert L Schlossman, Paul G Richardson, Aedin C Culhane, Richard W J Groen, Eric S Fischer, Francisca Vazquez, Aviad Tsherniak, William C Hahn, Joan Levy, Daniel Auclair, Jonathan D Licht, Jonathan J Keats, Lawrence H Boise, Benjamin L Ebert, James E Bradner, Nathanael S Gray, Constantine S Mitsiades
Heterobifunctional proteolysis-targeting chimeric compounds leverage the activity of E3 ligases to induce degradation of target oncoproteins and exhibit potent preclinical antitumor activity. To dissect the mechanisms regulating tumor cell sensitivity to different classes of pharmacological "degraders" of oncoproteins, we performed genome-scale CRISPR-Cas9-based gene editing studies. We observed that myeloma cell resistance to degraders of different targets (BET bromodomain proteins, CDK9) and operating through CRBN (degronimids) or VHL is primarily mediated by prevention of, rather than adaptation to, breakdown of the target oncoprotein; and this involves loss of function of the cognate E3 ligase or interactors/regulators of the respective cullin-RING ligase (CRL) complex...
January 5, 2021: Cell Reports
#24
JOURNAL ARTICLE
Seth Carbonneau, Sujata Sharma, Liaomin Peng, Vaisakh Rajan, Dominik Hainzl, Martin Henault, Chian Yang, Jacob Hale, Janine Shulok, John Tallarico, Jeff Porter, Jennifer L Brogdon, Glenn Dranoff, James E Bradner, Marc Hild, Carla P Guimaraes
The recent development of successful CAR (chimeric antigen receptor) T cell therapies has been accompanied by a need to better control potentially fatal toxicities that can arise from adverse immune reactions. Here we present a ligand-controlled CAR system, based on the IKZF3 ZF2 β-hairpin IMiD-inducible degron, which allows for the reversible control of expression levels of type I membrane proteins, including CARs. Testing this system in an established mouse xenotransplantation model for acute lymphoblastic leukemia, we validate the ability of the CAR19-degron to target and kill CD19-positive cells displaying complete control/clearance of the tumor...
June 17, 2021: Cell Chemical Biology
#25
JOURNAL ARTICLE
Evon Poon, Tong Liang, Yann Jamin, Susanne Walz, Colin Kwok, Anne Hakkert, Karen Barker, Zuzanna Urban, Khin Thway, Rhamy Zeid, Albert Hallsworth, Gary Box, Marli E Ebus, Marco P Licciardello, Yordan Sbirkov, Glori Lazaro, Elizabeth Calton, Barbara M Costa, Melanie Valenti, Alexis De Haven Brandon, Hannah Webber, Nicolas Tardif, Gilberto S Almeida, Rossitza Christova, Gunther Boysen, Mark W Richards, Giuseppe Barone, Anthony Ford, Richard Bayliss, Paul A Clarke, Johann De Bono, Nathanael S Gray, Julian Blagg, Simon P Robinson, Suzanne A Eccles, Daniella Zheleva, James E Bradner, Jan Molenaar, Igor Vivanco, Martin Eilers, Paul Workman, Charles Y Lin, Louis Chesler
The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 - a component of the transcription elongation complex P-TEFb - bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription...
October 5, 2020: Journal of Clinical Investigation
#26
JOURNAL ARTICLE
Behnam Nabet, Fleur M Ferguson, Bo Kyung A Seong, Miljan Kuljanin, Alan L Leggett, Mikaela L Mohardt, Amanda Robichaud, Amy S Conway, Dennis L Buckley, Joseph D Mancias, James E Bradner, Kimberly Stegmaier, Nathanael S Gray
Chemical biology strategies for directly perturbing protein homeostasis including the degradation tag (dTAG) system provide temporal advantages over genetic approaches and improved selectivity over small molecule inhibitors. We describe dTAGV -1, an exclusively selective VHL-recruiting dTAG molecule, to rapidly degrade FKBP12F36V -tagged proteins. dTAGV -1 overcomes a limitation of previously reported CRBN-recruiting dTAG molecules to degrade recalcitrant oncogenes, supports combination degrader studies and facilitates investigations of protein function in cells and mice...
September 18, 2020: Nature Communications
#27
JOURNAL ARTICLE
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
No abstract text is available yet for this article.
July 3, 2020: Journal of Biological Chemistry
#28
JOURNAL ARTICLE
Andrew Antolic, Hiroko Wakimoto, Zhe Jiao, Joshua M Gorham, Steven R DePalma, Madeleine E Lemieux, David A Conner, Da Young Lee, Jun Qi, Jonathan G Seidman, James E Bradner, Jonathan D Brown, Saptarsi M Haldar, Christine E Seidman, Michael A Burke
The bromodomain and extraterminal (BET) family comprises epigenetic reader proteins that are important regulators of inflammatory and hypertrophic gene expression in the heart. We previously identified the activation of proinflammatory gene networks as a key early driver of dilated cardiomyopathy (DCM) in transgenic mice expressing a mutant form of phospholamban (PLNR9C) - a genetic cause of DCM in humans. We hypothesized that BETs coactivate this inflammatory process, representing a critical node in the progression of DCM...
August 6, 2020: JCI Insight
#29
JOURNAL ARTICLE
Martin G Jaeger, Björn Schwalb, Sebastian D Mackowiak, Taras Velychko, Alexander Hanzl, Hana Imrichova, Matthias Brand, Benedikt Agerer, Someth Chorn, Behnam Nabet, Fleur M Ferguson, André C Müller, Andreas Bergthaler, Nathanael S Gray, James E Bradner, Christoph Bock, Denes Hnisz, Patrick Cramer, Georg E Winter
The Mediator complex directs signals from DNA-binding transcription factors to RNA polymerase II (Pol II). Despite this pivotal position, mechanistic understanding of Mediator in human cells remains incomplete. Here we quantified Mediator-controlled Pol II kinetics by coupling rapid subunit degradation with orthogonal experimental readouts. In agreement with a model of condensate-driven transcription initiation, large clusters of hypophosphorylated Pol II rapidly disassembled upon Mediator degradation. This was accompanied by a selective and pronounced disruption of cell-type-specifying transcriptional circuits, whose constituent genes featured exceptionally high rates of Pol II turnover...
July 2020: Nature Genetics
#30
JOURNAL ARTICLE
Shaokun Shu, Hua-Jun Wu, Jennifer Y Ge, Rhamy Zeid, Isaac S Harris, Bojana Jovanović, Katherine Murphy, Binbin Wang, Xintao Qiu, Jennifer E Endress, Jaime Reyes, Klothilda Lim, Alba Font-Tello, Sudeepa Syamala, Tengfei Xiao, Chandra Sekhar Reddy Chilamakuri, Evangelia K Papachristou, Clive D'Santos, Jayati Anand, Kunihiko Hinohara, Wei Li, Thomas O McDonald, Adrienne Luoma, Rebecca J Modiste, Quang-De Nguyen, Brittany Michel, Paloma Cejas, Cigall Kadoch, Jacob D Jaffe, Kai W Wucherpfennig, Jun Qi, X Shirley Liu, Henry Long, Myles Brown, Jason S Carroll, Joan S Brugge, James Bradner, Franziska Michor, Kornelia Polyak
BET bromodomain inhibitors (BBDIs) are candidate therapeutic agents for triple-negative breast cancer (TNBC) and other cancer types, but inherent and acquired resistance to BBDIs limits their potential clinical use. Using CRISPR and small-molecule inhibitor screens combined with comprehensive molecular profiling of BBDI response and resistance, we identified synthetic lethal interactions with BBDIs and genes that, when deleted, confer resistance. We observed synergy with regulators of cell cycle progression, YAP, AXL, and SRC signaling, and chemotherapeutic agents...
June 18, 2020: Molecular Cell
#31
JOURNAL ARTICLE
Aline Gaub, Bilal N Sheikh, M Felicia Basilicata, Marie Vincent, Mathilde Nizon, Cindy Colson, Matthew J Bird, James E Bradner, Julien Thevenon, Michael Boutros, Asifa Akhtar
Cells rely on a diverse repertoire of genes for maintaining homeostasis, but the transcriptional networks underlying their expression remain poorly understood. The MOF acetyltransferase-containing Non-Specific Lethal (NSL) complex is a broad transcription regulator. It is essential in Drosophila, and haploinsufficiency of the human KANSL1 subunit results in the Koolen-de Vries syndrome. Here, we perform a genome-wide RNAi screen and identify the BET protein BRD4 as an evolutionary conserved co-factor of the NSL complex...
May 7, 2020: Nature Communications
#32
JOURNAL ARTICLE
David Remillard, Dennis L Buckley, Hyuk-Soo Seo, Fleur M Ferguson, Sirano Dhe-Paganon, James E Bradner, Nathanael S Gray
Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2)...
October 10, 2019: ACS Medicinal Chemistry Letters
#33
JOURNAL ARTICLE
David P Labbé, Giorgia Zadra, Meng Yang, Jaime M Reyes, Charles Y Lin, Stefano Cacciatore, Ericka M Ebot, Amanda L Creech, Francesca Giunchi, Michelangelo Fiorentino, Habiba Elfandy, Sudeepa Syamala, Edward D Karoly, Mohammed Alshalalfa, Nicholas Erho, Ashley Ross, Edward M Schaeffer, Ewan A Gibb, Mandeep Takhar, Robert B Den, Jonathan Lehrer, R Jeffrey Karnes, Stephen J Freedland, Elai Davicioni, Daniel E Spratt, Leigh Ellis, Jacob D Jaffe, Anthony V DʼAmico, Philip W Kantoff, James E Bradner, Lorelei A Mucci, Jorge E Chavarro, Massimo Loda, Myles Brown
Systemic metabolic alterations associated with increased consumption of saturated fat and obesity are linked with increased risk of prostate cancer progression and mortality, but the molecular underpinnings of this association are poorly understood. Here, we demonstrate in a murine prostate cancer model, that high-fat diet (HFD) enhances the MYC transcriptional program through metabolic alterations that favour histone H4K20 hypomethylation at the promoter regions of MYC regulated genes, leading to increased cellular proliferation and tumour burden...
September 25, 2019: Nature Communications
#34
JOURNAL ARTICLE
Melusine Bleu, Swann Gaulis, Rui Lopes, Kathleen Sprouffske, Verena Apfel, Sjoerd Holwerda, Marco Pregnolato, Umut Yildiz, Valentina Cordoʹ, Antonella F M Dost, Judith Knehr, Walter Carbone, Felix Lohmann, Charles Y Lin, James E Bradner, Audrey Kauffmann, Luca Tordella, Guglielmo Roma, Giorgio G Galli
Transcription factor networks shape the gene expression programs responsible for normal cell identity and pathogenic state. Using Core Regulatory Circuitry analysis (CRC), we identify PAX8 as a candidate oncogene in Renal Cell Carcinoma (RCC) cells. Validation of large-scale functional genomic screens confirms that PAX8 silencing leads to decreased proliferation of RCC cell lines. Epigenomic analyses of PAX8-dependent cistrome demonstrate that PAX8 largely occupies active enhancer elements controlling genes involved in various metabolic pathways...
August 20, 2019: Nature Communications
#35
JOURNAL ARTICLE
Hiro Tatetsu, Chong Gao, Myriam Armant, Fei Wang, Shikiko Ueno, Xi Tian, Alex Federation, Jun Qi, James Bradner, Daniel G Tenen, Li Chai
Currently, there is a growing need for culturing hematopoietic stem/progenitor cells (HSPCs) in vitro for various clinical applications including gene therapy. Compared to cord blood (CB) CD34+ HSPCs, it is more challenging to maintain or expand peripheral blood mobilized stem/progenitor cell (PBSC) CD34+ cells ex vivo. To fill this knowledge gap, we have systematically surveyed 466 small molecule drug compounds for their potential in cytokine-dependent expansion of human CD34+ CD90+ HSPCs. We found that epigenetic modifiers, especially histone deacetylase inhibitors (HDACi), could preferentially maintain and expand these cells...
June 28, 2019: Experimental Hematology
#36
JOURNAL ARTICLE
Pratiti Bandopadhayay, Federica Piccioni, Ryan O'Rourke, Patricia Ho, Elizabeth M Gonzalez, Graham Buchan, Kenin Qian, Gabrielle Gionet, Emily Girard, Margo Coxon, Matthew G Rees, Lisa Brenan, Frank Dubois, Ofer Shapira, Noah F Greenwald, Melanie Pages, Amanda Balboni Iniguez, Brenton R Paolella, Alice Meng, Claire Sinai, Giovanni Roti, Neekesh V Dharia, Amanda Creech, Benjamin Tanenbaum, Prasidda Khadka, Adam Tracy, Hong L Tiv, Andrew L Hong, Shannon Coy, Rumana Rashid, Jia-Ren Lin, Glenn S Cowley, Fred C Lam, Amy Goodale, Yenarae Lee, Kathleen Schoolcraft, Francisca Vazquez, William C Hahn, Aviad Tsherniak, James E Bradner, Michael B Yaffe, Till Milde, Stefan M Pfister, Jun Qi, Monica Schenone, Steven A Carr, Keith L Ligon, Mark W Kieran, Sandro Santagata, James M Olson, Prafulla C Gokhale, Jacob D Jaffe, David E Root, Kimberly Stegmaier, Cory M Johannessen, Rameen Beroukhim
BET-bromodomain inhibition (BETi) has shown pre-clinical promise for MYC-amplified medulloblastoma. However, the mechanisms for its action, and ultimately for resistance, have not been fully defined. Here, using a combination of expression profiling, genome-scale CRISPR/Cas9-mediated loss of function and ORF/cDNA driven rescue screens, and cell-based models of spontaneous resistance, we identify bHLH/homeobox transcription factors and cell-cycle regulators as key genes mediating BETi's response and resistance...
June 3, 2019: Nature Communications
#37
JOURNAL ARTICLE
Sara Sdelci, André F Rendeiro, Philipp Rathert, Wanhui You, Jung-Ming G Lin, Anna Ringler, Gerald Hofstätter, Herwig P Moll, Bettina Gürtl, Matthias Farlik, Sandra Schick, Freya Klepsch, Matthew Oldach, Pisanu Buphamalai, Fiorella Schischlik, Peter Májek, Katja Parapatics, Christian Schmidl, Michael Schuster, Thomas Penz, Dennis L Buckley, Otto Hudecz, Richard Imre, Shuang-Yan Wang, Hans Michael Maric, Robert Kralovics, Keiryn L Bennett, Andre C Müller, Karl Mechtler, Jörg Menche, James E Bradner, Georg E Winter, Kristaps Klavins, Emilio Casanova, Christoph Bock, Johannes Zuber, Stefan Kubicek
The histone acetyl reader bromodomain-containing protein 4 (BRD4) is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1 (methylenetetrahydrofolate dehydrogenase, cyclohydrolase and formyltetrahydrofolate synthetase 1). We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4...
May 27, 2019: Nature Genetics
#38
JOURNAL ARTICLE
Aubrey L Miller, Samuel C Fehling, Patrick L Garcia, Tracy L Gamblin, Leona N Council, Robert C A M van Waardenburg, Eddy S Yang, James E Bradner, Karina J Yoon
BACKGROUND: DNA repair deficiency accumulates DNA damage and sensitizes tumor cells to PARP inhibitors (PARPi). Based on our observation that the BET inhibitor JQ1 increases levels of DNA damage, we evaluated the efficacy of JQ1 + the PARPi olaparib in preclinical models of pancreatic ductal adenocarcinoma (PDAC). We also addressed the mechanism by which JQ1 increased DNA damage. METHODS: The effect of JQ1 + olaparib on in vivo tumor growth was assessed with patient-derived xenograft (PDX) models of PDAC...
June 2019: EBioMedicine
#39
JOURNAL ARTICLE
Tanaz Sharifnia, Mathias J Wawer, Ting Chen, Qing-Yuan Huang, Barbara A Weir, Ann Sizemore, Matthew A Lawlor, Amy Goodale, Glenn S Cowley, Francisca Vazquez, Christopher J Ott, Joshua M Francis, Slim Sassi, Patricia Cogswell, Hadley E Sheppard, Tinghu Zhang, Nathanael S Gray, Paul A Clarke, Julian Blagg, Paul Workman, Josh Sommer, Francis Hornicek, David E Root, William C Hahn, James E Bradner, Kwok K Wong, Paul A Clemons, Charles Y Lin, Joanne D Kotz, Stuart L Schreiber
Chordoma is a primary bone cancer with no approved therapy1 . The identification of therapeutic targets in this disease has been challenging due to the infrequent occurrence of clinically actionable somatic mutations in chordoma tumors2,3 . Here we describe the discovery of therapeutically targetable chordoma dependencies via genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling. These systematic approaches reveal that the developmental transcription factor T (brachyury; TBXT) is the top selectively essential gene in chordoma, and that transcriptional cyclin-dependent kinase (CDK) inhibitors targeting CDK7/12/13 and CDK9 potently suppress chordoma cell proliferation...
February 2019: Nature Medicine
#40
JOURNAL ARTICLE
Matthew L Hemming, Matthew A Lawlor, Jessica L Andersen, Timothy Hagan, Otari Chipashvili, Thomas G Scott, Chandrajit P Raut, Ewa Sicinska, Scott A Armstrong, George D Demetri, James E Bradner
Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm characterized by activating mutations in the related receptor tyrosine kinases KIT and PDGFRA. GIST relies on expression of these unamplified receptor tyrosine kinase (RTK) genes through a large enhancer domain, resulting in high expression levels of the oncogene required for tumor growth. Although kinase inhibition is an effective therapy for many GIST patients, disease progression from kinase resistance mutations is common and no other effective classes of systemic therapy exist...
January 10, 2019: Cancer Research
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