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Sign Up#41
JOURNAL ARTICLE
Yusuke Tarumoto, Shan Lin, Jinhua Wang, Joseph P Milazzo, Yali Xu, Bin Lu, Zhaolin Yang, Yiliang Wei, Sofya Polyanskaya, Mark Wunderlich, Nathanael S Gray, Kimberly Stegmaier, Christopher R Vakoc
Lineage-defining transcription factors (TFs) are compelling targets for leukemia therapy, yet they are among the most challenging proteins to modulate directly with small molecules. We previously used CRISPR screening to identify a salt-inducible kinase 3 (SIK3) requirement for the growth of acute myeloid leukemia (AML) cell lines that overexpress the lineage TF myocyte enhancer factor (MEF2C). In this context, SIK3 maintains MEF2C function by directly phosphorylating histone deacetylase 4 (HDAC4), a repressive cofactor of MEF2C...
January 2, 2020: Blood
#42
JOURNAL ARTICLE
Francisco Caiado, Diogo Maia-Silva, Carolina Jardim, Nina Schmolka, Tânia Carvalho, Cláudia Reforço, Rita Faria, Branka Kolundzija, André E Simões, Tuncay Baubec, Christopher R Vakoc, Maria Gomes da Silva, Markus G Manz, Ton N Schumacher, Håkan Norell, Bruno Silva-Santos
Chemotherapy-resistant cancer recurrence is a major cause of mortality. In acute myeloid leukemia (AML), chemorefractory relapses result from the complex interplay between altered genetic, epigenetic and transcriptional states in leukemic cells. Here, we develop an experimental model system using in vitro lineage tracing coupled with exome, transcriptome and in vivo functional readouts to assess the AML population dynamics and associated molecular determinants underpinning chemoresistance development. We find that combining standard chemotherapeutic regimens with low doses of DNA methyltransferase inhibitors (DNMTi, hypomethylating drugs) prevents chemoresistant relapses...
November 1, 2019: Nature Communications
#43
JOURNAL ARTICLE
Fei Li, Zhong Deng, Ling Zhang, Caizhi Wu, Ying Jin, Inah Hwang, Olga Vladimirova, Libo Xu, Lynnie Yang, Bin Lu, Javaraju Dheekollu, Jian-Yi Li, Hua Feng, Jian Hu, Christopher R Vakoc, Haoqiang Ying, Jihye Paik, Paul M Lieberman, Hongwu Zheng
Loss of the histone H3.3-specific chaperone component ATRX or its partner DAXX frequently occurs in human cancers that employ alternative lengthening of telomeres (ALT) for chromosomal end protection, yet the underlying mechanism remains unclear. Here, we report that ATRX/DAXX does not serve as an immediate repressive switch for ALT. Instead, ATRX or DAXX depletion gradually induces telomere DNA replication dysfunction that activates not only homology-directed DNA repair responses but also cell cycle checkpoint control...
October 1, 2019: EMBO Journal
#44
JOURNAL ARTICLE
Katharina Ehrenhöfer-Wölfer, Teresa Puchner, Cornelia Schwarz, Janine Rippka, Silvia Blaha-Ostermann, Ursula Strobl, Alexandra Hörmann, Gerd Bader, Stefan Kornigg, Stephan Zahn, Wolfgang Sommergruber, Norbert Schweifer, Thomas Zichner, Andreas Schlattl, Ralph A Neumüller, Junwei Shi, Christopher R Vakoc, Manfred Kögl, Mark Petronczki, Norbert Kraut, Mark A Pearson, Simon Wöhrle
SMARCA4/BRG1 and SMARCA2/BRM, the two mutually exclusive catalytic subunits of the BAF complex, display a well-established synthetic lethal relationship in SMARCA4-deficient cancers. Using CRISPR-Cas9 screening, we identify SMARCA4 as a novel dependency in SMARCA2-deficient esophageal squamous cell carcinoma (ESCC) models, reciprocal to the known synthetic lethal interaction. Restoration of SMARCA2 expression alleviates the dependency on SMARCA4, while engineered loss of SMARCA2 renders ESCC models vulnerable to concomitant depletion of SMARCA4...
August 12, 2019: Scientific Reports
#45
JOURNAL ARTICLE
Jark Böttcher, David Dilworth, Ulrich Reiser, Ralph A Neumüller, Michael Schleicher, Mark Petronczki, Markus Zeeb, Nikolai Mischerikow, Abdellah Allali-Hassani, Magdalena M Szewczyk, Fengling Li, Steven Kennedy, Masoud Vedadi, Dalia Barsyte-Lovejoy, Peter J Brown, Kilian V M Huber, Catherine M Rogers, Carrow I Wells, Oleg Fedorov, Klaus Rumpel, Andreas Zoephel, Moriz Mayer, Tobias Wunberg, Dietrich Böse, Stephan Zahn, Heribert Arnhof, Helmut Berger, Christoph Reiser, Alexandra Hörmann, Teresa Krammer, Maja Corcokovic, Bernadette Sharps, Sandra Winkler, Daniela Häring, Xiao-Ling Cockcroft, Julian E Fuchs, Barbara Müllauer, Alexander Weiss-Puxbaum, Thomas Gerstberger, Guido Boehmelt, Christopher R Vakoc, Cheryl H Arrowsmith, Mark Pearson, Darryl B McConnell
Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM...
July 8, 2019: Nature Chemical Biology
#46
REVIEW
Marielle E Yohe, Christine M Heske, Elizabeth Stewart, Peter C Adamson, Nabil Ahmed, Cristina R Antonescu, Eleanor Chen, Natalie Collins, Alan Ehrlich, Rene L Galindo, Berkley E Gryder, Heidi Hahn, Sharon Hammond, Mark E Hatley, Douglas S Hawkins, Madeline N Hayes, Andrea Hayes-Jordan, Lee J Helman, Simone Hettmer, Myron S Ignatius, Charles Keller, Javed Khan, David G Kirsch, Corinne M Linardic, Philip J Lupo, Rossella Rota, Jack F Shern, Janet Shipley, Sivasish Sindiri, Stephen J Tapscott, Christopher R Vakoc, Leonard H Wexler, David M Langenau
Overall survival rates for pediatric patients with high-risk or relapsed rhabdomyosarcoma (RMS) have not improved significantly since the 1980s. Recent studies have identified a number of targetable vulnerabilities in RMS, but these discoveries have infrequently translated into clinical trials. We propose streamlining the process by which agents are selected for clinical evaluation in RMS. We believe that strong consideration should be given to the development of combination therapies that add biologically targeted agents to conventional cytotoxic drugs...
October 2019: Pediatric Blood & Cancer
#47
JOURNAL ARTICLE
Charles C Bell, Katie A Fennell, Yih-Chih Chan, Florian Rambow, Miriam M Yeung, Dane Vassiliadis, Luis Lara, Paul Yeh, Luciano G Martelotto, Aljosja Rogiers, Brandon E Kremer, Olena Barbash, Helai P Mohammad, Timothy M Johanson, Marian L Burr, Arindam Dhar, Natalie Karpinich, Luyi Tian, Dean S Tyler, Laura MacPherson, Junwei Shi, Nathan Pinnawala, Chun Yew Fong, Anthony T Papenfuss, Sean M Grimmond, Sarah-Jane Dawson, Rhys S Allan, Ryan G Kruger, Christopher R Vakoc, David L Goode, Shalin H Naik, Omer Gilan, Enid Y N Lam, Jean-Christophe Marine, Rab K Prinjha, Mark A Dawson
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state...
June 20, 2019: Nature Communications
#48
JOURNAL ARTICLE
Charles M Rudin, John T Poirier, Lauren Averett Byers, Caroline Dive, Afshin Dowlati, Julie George, John V Heymach, Jane E Johnson, Jonathan M Lehman, David MacPherson, Pierre P Massion, John D Minna, Trudy G Oliver, Vito Quaranta, Julien Sage, Roman K Thomas, Christopher R Vakoc, Adi F Gazdar
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
July 2019: Nature Reviews. Cancer
#49
JOURNAL ARTICLE
Xianjiang Lan, Eugene Khandros, Peng Huang, Scott A Peslak, Saurabh K Bhardwaj, Jeremy D Grevet, Osheiza Abdulmalik, Hongxin Wang, Cheryl A Keller, Belinda Giardine, Josue Baeza, Emily R Duffner, Osama El Demerdash, Xiaoli S Wu, Christopher R Vakoc, Benjamin A Garcia, Ross C Hardison, Junwei Shi, Gerd A Blobel
Reactivation of fetal hemoglobin (HbF) production benefits patients with sickle cell disease and β-thalassemia. To identify new HbF regulators that might be amenable to pharmacologic control, we screened a protein domain-focused CRISPR-Cas9 library targeting chromatin regulators, including BTB domain-containing proteins. Speckle-type POZ protein (SPOP), a substrate adaptor of the CUL3 ubiquitin ligase complex, emerged as a novel HbF repressor. Depletion of SPOP or overexpression of a dominant negative version significantly raised fetal globin messenger RNA and protein levels with minimal detrimental effects on normal erythroid maturation, as determined by transcriptome and proteome analyses...
May 28, 2019: Blood Advances
#50
JOURNAL ARTICLE
Narendra Bharathy, Noah E Berlow, Eric Wang, Jinu Abraham, Teagan P Settelmeyer, Jody E Hooper, Matthew N Svalina, Zia Bajwa, Martin W Goros, Brian S Hernandez, Johannes E Wolff, Ranadip Pal, Angela M Davies, Arya Ashok, Darnell Bushby, Maria Mancini, Christopher Noakes, Neal C Goodwin, Peter Ordentlich, James Keck, Douglas S Hawkins, Erin R Rudzinski, Atiya Mansoor, Theodore J Perkins, Christopher R Vakoc, Joel E Michalek, Charles Keller
BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models...
May 21, 2019: Skeletal Muscle
#51
REVIEW
Charles M Rudin, John T Poirier, Lauren Averett Byers, Caroline Dive, Afshin Dowlati, Julie George, John V Heymach, Jane E Johnson, Jonathan M Lehman, David MacPherson, Pierre P Massion, John D Minna, Trudy G Oliver, Vito Quaranta, Julien Sage, Roman K Thomas, Christopher R Vakoc, Adi F Gazdar
Small cell lung cancer (SCLC) is an exceptionally lethal malignancy for which more effective therapies are urgently needed. Several lines of evidence, from SCLC primary human tumours, patient-derived xenografts, cancer cell lines and genetically engineered mouse models, appear to be converging on a new model of SCLC subtypes defined by differential expression of four key transcription regulators: achaete-scute homologue 1 (ASCL1; also known as ASH1), neurogenic differentiation factor 1 (NeuroD1), yes-associated protein 1 (YAP1) and POU class 2 homeobox 3 (POU2F3)...
May 2019: Nature Reviews. Cancer
#52
JOURNAL ARTICLE
Erin R Aho, Jing Wang, Rocco D Gogliotti, Gregory C Howard, Jason Phan, Pankaj Acharya, Jonathan D Macdonald, Ken Cheng, Shelly L Lorey, Bin Lu, Sabine Wenzel, Audra M Foshage, Joseph Alvarado, Feng Wang, J Grace Shaw, Bin Zhao, April M Weissmiller, Lance R Thomas, Christopher R Vakoc, Matthew D Hall, Scott W Hiebert, Qi Liu, Shaun R Stauffer, Stephen W Fesik, William P Tansey
The chromatin-associated protein WDR5 is a promising target for pharmacological inhibition in cancer. Drug discovery efforts center on the blockade of the "WIN site" of WDR5, a well-defined pocket that is amenable to small molecule inhibition. Various cancer contexts have been proposed to be targets for WIN site inhibitors, but a lack of understanding of WDR5 target genes and of the primary effects of WIN site inhibitors hampers their utility. Here, by the discovery of potent WIN site inhibitors, we demonstrate that the WIN site links WDR5 to chromatin at a small cohort of loci, including a specific subset of ribosome protein genes...
March 12, 2019: Cell Reports
#53
JOURNAL ARTICLE
Bin Lu, Olaf Klingbeil, Yusuke Tarumoto, Tim D D Somerville, Yu-Han Huang, Yiliang Wei, Dorothy C Wai, Jason K K Low, Joseph P Milazzo, Xiaoli S Wu, Zhendong Cao, Xiaomei Yan, Osama E Demerdash, Gang Huang, Joel P Mackay, Justin B Kinney, Junwei Shi, Christopher R Vakoc
The Mixed Lineage Leukemia gene (MLL) is altered in leukemia by chromosomal translocations to produce oncoproteins composed of the MLL N-terminus fused to the C-terminus of a partner protein. Here, we used domain-focused CRISPR screening to identify ZFP64 as an essential transcription factor in MLL-rearranged leukemia. We show that the critical function of ZFP64 in leukemia is to maintain MLL expression via binding to the MLL promoter, which is the most enriched location of ZFP64 occupancy in the human genome...
December 10, 2018: Cancer Cell
#54
JOURNAL ARTICLE
Narendra Bharathy, Noah E Berlow, Eric Wang, Jinu Abraham, Teagan P Settelmeyer, Jody E Hooper, Matthew N Svalina, Yoshihiro Ishikawa, Keith Zientek, Zia Bajwa, Martin W Goros, Brian S Hernandez, Johannes E Wolff, Michelle A Rudek, Linping Xu, Nicole M Anders, Ranadip Pal, Alexandria P Harrold, Angela M Davies, Arya Ashok, Darnell Bushby, Maria Mancini, Christopher Noakes, Neal C Goodwin, Peter Ordentlich, James Keck, Douglas S Hawkins, Erin R Rudzinski, Bishwanath Chatterjee, Hans Peter Bächinger, Frederic G Barr, Jennifer Liddle, Benjamin A Garcia, Atiya Mansoor, Theodore J Perkins, Christopher R Vakoc, Joel E Michalek, Charles Keller
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood with an unmet clinical need for decades. A single oncogenic fusion gene is associated with treatment resistance and a 40 to 45% decrease in overall survival. We previously showed that expression of this PAX3:FOXO1 fusion oncogene in alveolar RMS (aRMS) mediates tolerance to chemotherapy and radiotherapy and that the class I-specific histone deacetylase (HDAC) inhibitor entinostat reduces PAX3:FOXO1 protein abundance. Here, we established the antitumor efficacy of entinostat with chemotherapy in various preclinical cell and mouse models and found that HDAC3 inhibition was the primary mechanism of entinostat-induced suppression of PAX3:FOXO1 abundance...
November 20, 2018: Science Signaling
#55
JOURNAL ARTICLE
Gerard L Brien, David Remillard, Junwei Shi, Matthew L Hemming, Jonathon Chabon, Kieran Wynne, Eugène T Dillon, Gerard Cagney, Guido Van Mierlo, Marijke P Baltissen, Michiel Vermeulen, Jun Qi, Stefan Fröhling, Nathanael S Gray, James E Bradner, Christopher R Vakoc, Scott A Armstrong
Synovial sarcoma tumours contain a characteristic fusion protein, SS18-SSX, which drives disease development. Targeting oncogenic fusion proteins presents an attractive therapeutic opportunity. However, SS18-SSX has proven intractable for therapeutic intervention. Using a domain-focused CRISPR screen we identified the bromodomain of BRD9 as a critical functional dependency in synovial sarcoma. BRD9 is a component of SS18-SSX containing BAF complexes in synovial sarcoma cells; and integration of BRD9 into these complexes is critical for cell growth...
November 15, 2018: ELife
#56
JOURNAL ARTICLE
Tim D D Somerville, Yali Xu, Koji Miyabayashi, Hervé Tiriac, Cristian R Cleary, Diogo Maia-Silva, Joseph P Milazzo, David A Tuveson, Christopher R Vakoc
The aberrant expression of squamous lineage markers in pancreatic ductal adenocarcinoma (PDA) has been correlated with poor clinical outcomes. However, the functional role of this putative transdifferentiation event in PDA pathogenesis remains unclear. Here, we show that expression of the transcription factor TP63 (ΔNp63) is sufficient to install and sustain the enhancer landscape and transcriptional signature of the squamous lineage in human PDA cells. We also demonstrate that TP63-driven enhancer reprogramming promotes aggressive tumor phenotypes, including enhanced cell motility and invasion, and an accelerated growth of primary PDA tumors and metastases in vivo...
November 13, 2018: Cell Reports
#57
EDITORIAL
Christopher R Vakoc, Alex Kentsis
No abstract text is available yet for this article.
August 17, 2018: Oncotarget
#58
JOURNAL ARTICLE
Ana Banito, Xiang Li, Aimée N Laporte, Jae-Seok Roe, Francisco Sanchez-Vega, Chun-Hao Huang, Amanda R Dancsok, Katerina Hatzi, Chi-Chao Chen, Darjus F Tschaharganeh, Rohit Chandwani, Nilgun Tasdemir, Kevin B Jones, Mario R Capecchi, Christopher R Vakoc, Nikolaus Schultz, Marc Ladanyi, Torsten O Nielsen, Scott W Lowe
No abstract text is available yet for this article.
August 13, 2018: Cancer Cell
#59
JOURNAL ARTICLE
Alexandra Hörmann, Barbara Hopfgartner, Thomas Köcher, Maja Corcokovic, Teresa Krammer, Christoph Reiser, Gerd Bader, Junwei Shi, Katharina Ehrenhöfer, Simon Wöhrle, Norbert Schweifer, Christopher R Vakoc, Norbert Kraut, Mark Pearson, Mark Petronczki, Ralph A Neumüller
Genotype specific vulnerabilities of cancer cells constitute a promising strategy for the development of new therapeutics. Deletions of non-essential genes in tumors can generate unique vulnerabilities which could be exploited therapeutically. The MTAP gene is recurrently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A . Recent studies have uncovered an increased dependency of MTAP -deleted cancer cells on the function of a PRMT5 containing complex, including WDR77, PRMT5 and the kinase RIOK1...
June 19, 2018: Oncotarget
#60
JOURNAL ARTICLE
Maria Paz Zafra, Emma M Schatoff, Alyna Katti, Miguel Foronda, Marco Breinig, Anabel Y Schweitzer, Amber Simon, Teng Han, Sukanya Goswami, Emma Montgomery, Jordana Thibado, Edward R Kastenhuber, Francisco J Sánchez-Rivera, Junwei Shi, Christopher R Vakoc, Scott W Lowe, Darjus F Tschaharganeh, Lukas E Dow
CRISPR base editing enables the creation of targeted single-base conversions without generating double-stranded breaks. However, the efficiency of current base editors is very low in many cell types. We reengineered the sequences of BE3, BE4Gam, and xBE3 by codon optimization and incorporation of additional nuclear-localization sequences. Our collection of optimized constitutive and inducible base-editing vector systems dramatically improves the efficiency by which single-nucleotide variants can be created...
October 2018: Nature Biotechnology
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