keyword
https://read.qxmd.com/read/35576971/oca-t1-and-oca-t2-are-coactivators-of-pou2f3-in-the-tuft-cell-lineage
#21
JOURNAL ARTICLE
Xiaoli S Wu, Xue-Yan He, Jonathan J Ipsaro, Yu-Han Huang, Jonathan B Preall, David Ng, Yan Ting Shue, Julien Sage, Mikala Egeblad, Leemor Joshua-Tor, Christopher R Vakoc
Tuft cells are a rare chemosensory lineage that coordinates immune and neural responses to foreign pathogens in mucosal tissues1 . Recent studies have also revealed tuft-cell-like human tumours2,3 , particularly as a variant of small-cell lung cancer. Both normal and neoplastic tuft cells share a genetic requirement for the transcription factor POU2F3 (refs. 2,4 ), although the transcriptional mechanisms that generate this cell type are poorly understood. Here we show that binding of POU2F3 to the uncharacterized proteins C11orf53 and COLCA2 (renamed here OCA-T1/POU2AF2 and OCA-T2/POU2AF3, respectively) is critical in the tuft cell lineage...
July 2022: Nature
https://read.qxmd.com/read/35513429/comparative-optimization-of-combinatorial-crispr-screens
#22
JOURNAL ARTICLE
Ruitong Li, Olaf Klingbeil, Davide Monducci, Michael J Young, Diego J Rodriguez, Zaid Bayyat, Joshua M Dempster, Devishi Kesar, Xiaoping Yang, Mahdi Zamanighomi, Christopher R Vakoc, Takahiro Ito, William R Sellers
Combinatorial CRISPR technologies have emerged as a transformative approach to systematically probe genetic interactions and dependencies of redundant gene pairs. However, the performance of different functional genomic tools for multiplexing sgRNAs vary widely. Here, we generate and benchmark ten distinct pooled combinatorial CRISPR libraries targeting paralog pairs to optimize digenic knockout screens. Libraries composed of dual Streptococcus pyogenes Cas9 (spCas9), orthogonal spCas9 and Staphylococcus aureus (saCas9), and enhanced Cas12a from Acidaminococcus were evaluated...
May 5, 2022: Nature Communications
https://read.qxmd.com/read/35094009/smarca4-biology-in-alveolar-rhabdomyosarcoma
#23
JOURNAL ARTICLE
Narendra Bharathy, Megan M Cleary, Jin-Ah Kim, Kiyo Nagamori, Kenneth A Crawford, Eric Wang, Debarya Saha, Teagan P Settelmeyer, Reshma Purohit, Damianos Skopelitis, Kenneth Chang, Jessica A Doran, C Ward Kirschbaum, Suriya Bharathy, Davis W Crews, Matthew E Randolph, Anthony N Karnezis, Lisa Hudson-Price, Jyotsna Dhawan, Joel E Michalek, Alessio Ciulli, Christopher R Vakoc, Charles Keller
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and phenocopies a muscle precursor that fails to undergo terminal differentiation. The alveolar subtype (ARMS) has the poorest prognosis and represents the greatest unmet medical need for RMS. Emerging evidence supports the role of epigenetic dysregulation in RMS. Here we show that SMARCA4/BRG1, an ATP-dependent chromatin remodeling enzyme of the SWI/SNF complex, is prominently expressed in primary tumors from ARMS patients and cell cultures...
March 2022: Oncogene
https://read.qxmd.com/read/35021089/scp4-stk35-pdik1l-complex-is-a-dual-phospho-catalytic-signaling-dependency-in-acute-myeloid-leukemia
#24
JOURNAL ARTICLE
Sofya A Polyanskaya, Rosamaria Y Moreno, Bin Lu, Ruopeng Feng, Yu Yao, Seema Irani, Olaf Klingbeil, Zhaolin Yang, Yiliang Wei, Osama E Demerdash, Lukas A Benjamin, Mitchell J Weiss, Yan Jessie Zhang, Christopher R Vakoc
Acute myeloid leukemia (AML) cells rely on phospho-signaling pathways to gain unlimited proliferation potential. Here, we use domain-focused CRISPR screening and identify the nuclear phosphatase SCP4 as a dependency in AML, yet this enzyme is dispensable in normal hematopoietic progenitor cells. Using CRISPR exon scanning and gene complementation assays, we show that the catalytic function of SCP4 is essential in AML. Through mass spectrometry analysis of affinity-purified complexes, we identify the kinase paralogs STK35 and PDIK1L as binding partners and substrates of the SCP4 phosphatase domain...
January 11, 2022: Cell Reports
https://read.qxmd.com/read/34836971/baf-complexes-drive-proliferation-and-block-myogenic-differentiation-in-fusion-positive-rhabdomyosarcoma
#25
JOURNAL ARTICLE
Dominik Laubscher, Berkley E Gryder, Benjamin D Sunkel, Thorkell Andresson, Marco Wachtel, Sudipto Das, Bernd Roschitzki, Witold Wolski, Xiaoli S Wu, Hsien-Chao Chou, Young K Song, Chaoyu Wang, Jun S Wei, Meng Wang, Xinyu Wen, Quy Ai Ngo, Joana G Marques, Christopher R Vakoc, Beat W Schäfer, Benjamin Z Stanton, Javed Khan
Rhabdomyosarcoma (RMS) is a pediatric malignancy of skeletal muscle lineage. The aggressive alveolar subtype is characterized by t(2;13) or t(1;13) translocations encoding for PAX3- or PAX7-FOXO1 chimeric transcription factors, respectively, and are referred to as fusion positive RMS (FP-RMS). The fusion gene alters the myogenic program and maintains the proliferative state while blocking terminal differentiation. Here, we investigated the contributions of chromatin regulatory complexes to FP-RMS tumor maintenance...
November 26, 2021: Nature Communications
https://read.qxmd.com/read/34556174/ace-a-probabilistic-model-for-characterizing-gene-level-essentiality-in-crispr-screens
#26
JOURNAL ARTICLE
Elizabeth R Hutton, Christopher R Vakoc, Adam Siepel
High-throughput CRISPR-Cas9 knockout screens are widely used to evaluate gene essentiality in cancer research. Here we introduce a probabilistic modeling framework, Analysis of CRISPR-based Essentiality (ACE), that accounts for multiple sources of variation in CRISPR-Cas9 screens and enables new statistical tests for essentiality. We show using simulations that ACE is effective at predicting both absolute and differential essentiality. When applied to publicly available data, ACE identifies known and novel candidates for genotype-specific essentiality, including RNA m6 -A methyltransferases that exhibit enhanced essentiality in the presence of inactivating TP53 mutations...
September 23, 2021: Genome Biology
https://read.qxmd.com/read/34531253/slc5a3-dependent-myo-inositol-auxotrophy-in-acute-myeloid-leukemia
#27
JOURNAL ARTICLE
Yiliang Wei, Yu-Han Huang, Damianos S Skopelitis, Shruti V Iyer, Ana S H Costa, Zhaolin Yang, Melissa Kramer, Emmalee R Adelman, Olaf Klingbeil, Osama E Demerdash, Sofya A Polyanskaya, Kenneth Chang, Sara Goodwin, Emily Hodges, W Richard McCombie, Maria E Figueroa, Christopher R Vakoc
An enhanced requirement for nutrients is a hallmark property of cancer cells. Here, we optimized an in vivo genetic screening strategy in acute myeloid leukemia (AML), which led to the identification of the myo-inositol transporter SLC5A3 as a dependency in this disease. We demonstrate that SLC5A3 is essential to support a myo-inositol auxotrophy in AML. The commonality among SLC5A3-dependent AML lines is the transcriptional silencing of ISYNA1 , which encodes the rate-limiting enzyme for myo-inositol biosynthesis, inositol-3-phosphate synthase 1...
February 2022: Cancer Discovery
https://read.qxmd.com/read/34016956/superior-efficacy-of-co-targeting-gfi1-kdm1a-and-brd4-against-aml-and-post-mpn-secondary-aml-cells
#28
JOURNAL ARTICLE
Warren Fiskus, Christopher P Mill, Behnam Nabet, Dimuthu Perera, Christine Birdwell, Taghi Manshouri, Bernardo Lara, Tapan M Kadia, Courtney DiNardo, Koichi Takahashi, Naval Daver, Prithviraj Bose, Lucia Masarova, Naveen Pemmaraju, Steven Kornblau, Gautam Borthakur, Guillermo Montalban-Bravo, Guillermo Garcia Manero, Sunil Sharma, Matthew Stubbs, Xiaoping Su, Michael R Green, Cristian Coarfa, Srdan Verstovsek, Joseph D Khoury, Christopher R Vakoc, Kapil N Bhalla
There is an unmet need to overcome nongenetic therapy-resistance to improve outcomes in AML, especially post-myeloproliferative neoplasm (MPN) secondary (s) AML. Studies presented describe effects of genetic knockout, degradation or small molecule targeted-inhibition of GFI1/LSD1 on active enhancers, altering gene-expressions and inducing differentiation and lethality in AML and (MPN) sAML cells. A protein domain-focused CRISPR screen in LSD1 (KDM1A) inhibitor (i) treated AML cells, identified BRD4, MOZ, HDAC3 and DOT1L among the codependencies...
May 20, 2021: Blood Cancer Journal
https://read.qxmd.com/read/33893150/transcriptional-silencing-of-aldh2-confers-a-dependency-on-fanconi-anemia-proteins-in-acute-myeloid-leukemia
#29
JOURNAL ARTICLE
Zhaolin Yang, Xiaoli S Wu, Yiliang Wei, Sofya A Polyanskaya, Shruti V Iyer, Moonjung Jung, Francis P Lach, Emmalee R Adelman, Olaf Klingbeil, Joseph P Milazzo, Melissa Kramer, Osama E Demerdash, Kenneth Chang, Sara Goodwin, Emily Hodges, W Richard McCombie, Maria E Figueroa, Agata Smogorzewska, Christopher R Vakoc
Hundreds of genes become aberrantly silenced in acute myeloid leukemia (AML), with most of these epigenetic changes being of unknown functional consequence. Here, we demonstrate how gene silencing can lead to an acquired dependency on the DNA repair machinery in AML. We make this observation by profiling the essentiality of the ubiquitination machinery in cancer cell lines using domain-focused CRISPR screening, which revealed Fanconi anemia (FA) proteins UBE2T and FANCL as unique dependencies in AML. We demonstrate that these dependencies are due to a synthetic lethal interaction between FA proteins and aldehyde dehydrogenase 2 (ALDH2), which function in parallel pathways to counteract the genotoxicity of endogenous aldehydes...
September 2021: Cancer Discovery
https://read.qxmd.com/read/33536596/an-epigenetic-tipping-point-in-cancer-comes-under-the-microscope
#30
COMMENT
Martyna W Sroka, Christopher R Vakoc
No abstract text is available yet for this article.
February 2021: Nature
https://read.qxmd.com/read/33522487/the-human-origin-recognition-complex-is-essential-for-pre-rc-assembly-mitosis-and-maintenance-of-nuclear-structure
#31
JOURNAL ARTICLE
Hsiang-Chen Chou, Kuhulika Bhalla, Osama El Demerdesh, Olaf Klingbeil, Kaarina Hanington, Sergey Aganezov, Peter Andrews, Habeeb Alsudani, Kenneth Chang, Christopher R Vakoc, Michael C Schatz, W Richard McCombie, Bruce Stillman
The origin recognition complex (ORC) cooperates with CDC6, MCM2-7, and CDT1 to form pre-RC complexes at origins of DNA replication. Here, using tiling-sgRNA CRISPR screens, we report that each subunit of ORC and CDC6 is essential in human cells. Using an auxin-inducible degradation system, we created stable cell lines capable of ablating ORC2 rapidly, revealing multiple cell division cycle phenotypes. The primary defects in the absence of ORC2 were cells encountering difficulty in initiating DNA replication or progressing through the cell division cycle due to reduced MCM2-7 loading onto chromatin in G1 phase...
February 1, 2021: ELife
https://read.qxmd.com/read/32703770/intraductal-transplantation-models-of-human-pancreatic-ductal-adenocarcinoma-reveal-progressive-transition-of-molecular-subtypes
#32
JOURNAL ARTICLE
Koji Miyabayashi, Lindsey A Baker, Astrid Deschenes, Benno Traub, Giuseppina Caligiuri, Dennis Plenker, Brinda Alagesan, Pascal Belleau, Siran Li, Jude Kendall, Gun Ho Jang, Risa Karakida Kawaguchi, Tim D D Somerville, Herve Tiriac, Chang-Il Hwang, Richard A Burkhart, Nicholas J Roberts, Laura D Wood, Ralph H Hruban, Jesse Gillis, Alexander Krasnitz, Christopher R Vakoc, Michael Wigler, Faiyaz Notta, Steven Gallinger, Youngkyu Park, David A Tuveson
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy, with little improvement in patient outcomes over the past decades. Recently, subtypes of pancreatic cancer with different prognoses have been elaborated, however the inability to model these subtypes has precluded mechanistic investigation of their origins. Here, we present a xenotransplantation model of PDAC in which neoplasms originate from patient-derived organoids injected directly into murine pancreatic ducts. Our model enables distinction of the two main PDAC subtypes: intraepithelial neoplasms from this model progress in an indolent or invasive manner representing the classical or basal-like subtypes of PDAC, respectively...
July 23, 2020: Cancer Discovery
https://read.qxmd.com/read/32633781/soat1-promotes-mevalonate-pathway-dependency-in-pancreatic-cancer
#33
JOURNAL ARTICLE
Tobiloba E Oni, Giulia Biffi, Lindsey A Baker, Yuan Hao, Claudia Tonelli, Tim D D Somerville, Astrid Deschênes, Pascal Belleau, Chang-Il Hwang, Francisco J Sánchez-Rivera, Hilary Cox, Erin Brosnan, Abhishek Doshi, Rebecca P Lumia, Kimia Khaledi, Youngkyu Park, Lloyd C Trotman, Scott W Lowe, Alexander Krasnitz, Christopher R Vakoc, David A Tuveson
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, and new therapies are needed. Altered metabolism is a cancer vulnerability, and several metabolic pathways have been shown to promote PDAC. However, the changes in cholesterol metabolism and their role during PDAC progression remain largely unknown. Here we used organoid and mouse models to determine the drivers of altered cholesterol metabolism in PDAC and the consequences of its disruption on tumor progression. We identified sterol O-acyltransferase 1 (SOAT1) as a key player in sustaining the mevalonate pathway by converting cholesterol to inert cholesterol esters, thereby preventing the negative feedback elicited by unesterified cholesterol...
September 7, 2020: Journal of Experimental Medicine
https://read.qxmd.com/read/32424274/a-pliable-er%C3%AE-cistrome-evades-therapy
#34
JOURNAL ARTICLE
Xiaoli S Wu, Christopher R Vakoc
No abstract text is available yet for this article.
May 18, 2020: Nature Cell Biology
https://read.qxmd.com/read/32416589/miswired-enhancer-logic-drives-a-cancer-of-the-muscle-lineage
#35
JOURNAL ARTICLE
Berkley E Gryder, Marco Wachtel, Kenneth Chang, Osama El Demerdash, Nicholas G Aboreden, Wardah Mohammed, Winston Ewert, Silvia Pomella, Rossella Rota, Jun S Wei, Young Song, Benjamin Z Stanton, Beat Schäfer, Christopher R Vakoc, Javed Khan
Core regulatory transcription factors (CR TFs) establish enhancers with logical ordering during embryogenesis and development. Here we report that in fusion-positive rhabdomyosarcoma, a cancer of the muscle lineage, the chief oncogene PAX3-FOXO1 is driven by a translocated FOXO1 super enhancer (SE) restricted to a late stage of myogenesis. Using chromatin conformation capture techniques, we demonstrate that the extensive FOXO1 cis-regulatory domain interacts with PAX3. Furthermore, RNA sequencing and chromatin immunoprecipitation sequencing data in tumors bearing rare PAX translocations implicate enhancer miswiring across all fusion-positive tumors...
May 22, 2020: IScience
https://read.qxmd.com/read/32385160/zbed2-is-an-antagonist-of-interferon-regulatory-factor-1-and-modifies-cell-identity-in-pancreatic-cancer
#36
JOURNAL ARTICLE
Tim D D Somerville, Yali Xu, Xiaoli S Wu, Diogo Maia-Silva, Stella K Hur, Larissa M N de Almeida, Jonathan B Preall, Peter K Koo, Christopher R Vakoc
Lineage plasticity is a prominent feature of pancreatic ductal adenocarcinoma (PDA) cells, which can occur via deregulation of lineage-specifying transcription factors. Here, we show that the zinc finger protein ZBED2 is aberrantly expressed in PDA and alters tumor cell identity in this disease. Unexpectedly, our epigenomic experiments reveal that ZBED2 is a sequence-specific transcriptional repressor of IFN-stimulated genes, which occurs through antagonism of IFN regulatory factor 1 (IRF1)-mediated transcriptional activation at cooccupied promoter elements...
May 8, 2020: Proceedings of the National Academy of Sciences of the United States of America
https://read.qxmd.com/read/32329713/squamous-trans-differentiation-of-pancreatic-cancer-cells-promotes-stromal-inflammation
#37
JOURNAL ARTICLE
Tim Dd Somerville, Giulia Biffi, Juliane Daßler-Plenker, Stella K Hur, Xue-Yan He, Krysten E Vance, Koji Miyabayashi, Yali Xu, Diogo Maia-Silva, Olaf Klingbeil, Osama E Demerdash, Jonathan B Preall, Michael A Hollingsworth, Mikala Egeblad, David A Tuveson, Christopher R Vakoc
A highly aggressive subset of pancreatic ductal adenocarcinomas undergo trans-differentiation into the squamous lineage during disease progression. Here, we investigated whether squamous trans-differentiation of human and mouse pancreatic cancer cells can influence the phenotype of non-neoplastic cells in the tumor microenvironment. Conditioned media experiments revealed that squamous pancreatic cancer cells secrete factors that recruit neutrophils and convert pancreatic stellate cells into cancer-associated fibroblasts (CAFs) that express inflammatory cytokines at high levels...
April 24, 2020: ELife
https://read.qxmd.com/read/32018053/new-approaches-to-sclc-therapy-from-the-laboratory-to-the-clinic
#38
REVIEW
John T Poirier, Julie George, Taofeek K Owonikoko, Anton Berns, Elisabeth Brambilla, Lauren A Byers, David Carbone, Huanhuan J Chen, Camilla L Christensen, Caroline Dive, Anna F Farago, Ramaswamy Govindan, Christine Hann, Matthew D Hellmann, Leora Horn, Jane E Johnson, Young S Ju, Sumin Kang, Mark Krasnow, James Lee, Se-Hoon Lee, Jonathan Lehman, Benjamin Lok, Christine Lovly, David MacPherson, David McFadden, John Minna, Matthew Oser, Keunchil Park, Kwon-Sik Park, Yves Pommier, Vito Quaranta, Neal Ready, Julien Sage, Giorgio Scagliotti, Martin L Sos, Kate D Sutherland, William D Travis, Christopher R Vakoc, Sarah J Wait, Ignacio Wistuba, Kwok Kin Wong, Hua Zhang, Jillian Daigneault, Jacinta Wiens, Charles M Rudin, Trudy G Oliver
The outcomes of patients with SCLC have not yet been substantially impacted by the revolution in precision oncology, primarily owing to a paucity of genetic alterations in actionable driver oncogenes. Nevertheless, systemic therapies that include immunotherapy are beginning to show promise in the clinic. Although, these results are encouraging, many patients do not respond to, or rapidly recur after, current regimens, necessitating alternative or complementary therapeutic strategies. In this review, we discuss ongoing investigations into the pathobiology of this recalcitrant cancer and the therapeutic vulnerabilities that are exposed by the disease state...
April 2020: Journal of Thoracic Oncology
https://read.qxmd.com/read/31784732/histone-hyperacetylation-disrupts-core-gene-regulatory-architecture-in-rhabdomyosarcoma
#39
JOURNAL ARTICLE
Berkley E Gryder, Silvia Pomella, Carly Sayers, Xiaoli S Wu, Young Song, Anna M Chiarella, Sukriti Bagchi, Hsien-Chao Chou, Ranu S Sinniah, Ashley Walton, Xinyu Wen, Rossella Rota, Nathaniel A Hathaway, Keji Zhao, Jiji Chen, Christopher R Vakoc, Jack F Shern, Benjamin Z Stanton, Javed Khan
Core regulatory transcription factors (CR TFs) orchestrate the placement of super-enhancers (SEs) to activate transcription of cell-identity specifying gene networks, and are critical in promoting cancer. Here, we define the core regulatory circuitry of rhabdomyosarcoma and identify critical CR TF dependencies. These CR TFs build SEs that have the highest levels of histone acetylation, yet paradoxically the same SEs also harbor the greatest amounts of histone deacetylases. We find that hyperacetylation selectively halts CR TF transcription...
December 2019: Nature Genetics
https://read.qxmd.com/read/31772183/author-correction-lineage-tracing-of-acute-myeloid-leukemia-reveals-the-impact-of-hypomethylating-agents-on-chemoresistance-selection
#40
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
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
November 26, 2019: Nature Communications
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