DOCSLIB.ORG

Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Clinicogenomic Analysis of FGFR2-Rearranged Cholangiocarcinoma Identifies Author Manuscript Published OnlineFirst on November 20, 2020; DOI: 10.1158/2159-8290.CD-20-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Clinicogenomic analysis of FGFR2-rearranged cholangiocarcinoma identifies correlates of response and mechanisms of resistance to pemigatinib Ian M. Silverman,1 Antoine Hollebecque,2 Luc Friboulet,2 Sherry Owens,1 Robert C. Newton,1 Huiling Zhen,3 Luis Féliz,4 Camilla Zecchetto,5 Davide Melisi,5 and Timothy C. Burn1 1Incyte Research Institute, Wilmington, Delaware. 2Institut Gustave Roussy, Villejuif, France. 3Incyte Corporation, Wilmington, Delaware. 4Incyte Biosciences International Sàrl, Morges, Switzerland. 5Digestive Molecular Clinical Oncology Research Unit, Section of Medical Oncology, Università degli Studi di Verona, Verona, Italy. Running Title: Genomic Profiling in FGFR2-Rearranged Cholangiocarcinoma Keywords: pemigatinib, FGFR2, precision medicine, genomic profiling, cholangiocarcinoma Additional Information Financial Support: This study was sponsored by Incyte Corporation (Wilmington, Delaware). Corresponding Author: Timothy C. Burn, 1801 Augustine Cut-Off, Wilmington, DE 19803 W: 302 498 6787; [email protected] Conflict of Interest: 1 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 20, 2020; DOI: 10.1158/2159-8290.CD-20-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. I.M. Silverman has employment with and owns stocks from Incyte Corporation. A. Hollebecque is a paid consultant for Debiopharm and Incyte Corporation. L. Friboulet received research funding from Debiopharm. S. Owens has employment with and owns stocks from Incyte Corporation. R.C. Newton had employment with Incyte Corporation at the time of this work and owns stock from Incyte Corporation. H. Zhen has employment with and owns stocks from Incyte Corporation. L. Féliz has employment with and owns stocks from Incyte Corporation. C. Zecchetto declares no potential conflicts of interest. D. Melisi received research funding from Celgene, Evotec, Incyte Corporation, and Shire; and had a consulting role at Baxter, Eli Lilly, Evotec, iOnctura, and Shire, which was unrelated to the present work. T.C. Burn has employment with and owns stocks from Incyte Corporation. 2 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 20, 2020; DOI: 10.1158/2159-8290.CD-20-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Pemigatinib, a selective fibroblast growth factor receptor (FGFR) 1–3 inhibitor, has demonstrated antitumor activity in FIGHT-202, a phase 2 study in patients with cholangiocarcinoma harboring FGFR2 fusions/rearrangements, and has gained regulatory approval in the United States. Eligibility for FIGHT-202 was assessed using genomic profiling; here, these data were utilized to characterize the genomic landscape of cholangiocarcinoma, and to uncover unique molecular features of patients harboring FGFR2 rearrangements. The results highlight the high percentage of patients with cholangiocarcinoma harboring potentially actionable genomic alterations and the diversity in gene partners that rearrange with FGFR2. Clinicogenomic analysis of pemigatinib-treated patients identified mechanisms of primary and acquired resistance. Genomic subsets of patients with other potentially actionable FGF/FGFR alterations were also identified. Our study provides a framework for molecularly-guided clinical trials and underscores the importance of genomic profiling to enable a deeper understanding of the molecular basis for response and nonresponse to targeted therapy. 3 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 20, 2020; DOI: 10.1158/2159-8290.CD-20-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Statement of Significance We utilized genomic profiling data from FIGHT-202 to gain insights into the genomic landscape of cholangiocarcinoma, to understand the molecular diversity of patients with FGFR2 fusions or rearrangements, and to interrogate the clinicogenomics of patients treated with pemigatinib. Our study highlights the utility of genomic profiling in clinical trials. 4 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 20, 2020; DOI: 10.1158/2159-8290.CD-20-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. INTRODUCTION Cholangiocarcinoma is the most common primary malignancy of the bile duct, and accounts for 3% of all gastrointestinal tumors (1,2). Cholangiocarcinoma comprises a group of heterogeneous tumors categorized as intrahepatic and extrahepatic (perihilar and distal), based on biliary tract location (2). Incidence and mortality rates of cholangiocarcinoma have increased over the past decades, most notably for intrahepatic cholangiocarcinoma (3-5). The prognosis of patients with cholangiocarcinoma is poor; surgery is the only potentially curative therapeutic option (6). However, as most patients present with advanced disease, only approximately one-third of newly diagnosed patients qualify for surgery. Among patients who are qualified to undergo potentially curative resection, most (~76%) will experience a relapse within 2 years (7). For patients with locally advanced or metastatic disease, the standard-of-care first-line systemic treatment is chemotherapy with gemcitabine plus cisplatin (8). There is no established standard of care following first-line chemotherapy failure, and second-line chemotherapy shows limited efficacy in patients with advanced biliary tract cancer (9-11). Genomic profiling, based on next-generation sequencing (NGS) of a panel of genes known to be altered in cancer, allows for the simultaneous detection of numerous genomic alteration types, including mutations, copy number alterations, and fusions or rearrangements (12). Therefore, this technique provides a powerful basis for guiding choice of targeted therapy, improved diagnosis, and identification of prognostic and predictive biomarkers. Genomic analysis of patients with cholangiocarcinoma has revealed alterations of targetable oncogenes in almost 50% of patients (13), with recurrent alterations in IDH1 and FGFR2 occurring almost exclusively in patients with intrahepatic cholangiocarcinoma compared with extrahepatic cholangiocarcinoma (13-15). Specifically, FGFR2 fusions or rearrangements are observed in 5 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 20, 2020; DOI: 10.1158/2159-8290.CD-20-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 10% to 16% of patients with intrahepatic cholangiocarcinoma (16-18). FGFR2 genomic alterations (GAs), including activating point mutations, fusions, and rearrangements, are known oncogenic drivers and provide a molecular signature to identify patients who may benefit from inhibition of FGFR2 tyrosine kinase activity (19,20). Therefore, NGS-based assays are used to comprehensively identify patients with cholangiocarcinoma that may benefit from targeted therapies. Pemigatinib is the first targeted therapeutic agent approved in the United States for use in cholangiocarcinoma with FGFR2 fusions or rearrangements. Pemigatinib is a selective, potent, oral, competitive inhibitor of FGFR1, 2, and 3 that inhibits receptor autophosphorylation and subsequent activation of FGF/FGFR-mediated signaling networks, leading to an inhibition of tumor cell growth in FGFR-driven cancers (21). The FIbroblast Growth factor receptor inhibitor in oncology and Hematology Trial (FIGHT-202; NCT02924376) is a phase 2, multicenter, open- label study of pemigatinib monotherapy in previously treated patients with locally advanced, metastatic, or surgically unresectable cholangiocarcinoma, including patients with FGFR2 fusions or rearrangements (22). In this study, patients were initially prescreened prior to enrollment for FGF/FGFR alterations including amplifications, mutations, fusions, or rearrangements. The primary analysis of 107 patients included only patients harboring FGFR2 fusions or rearrangements. In these patients, pemigatinib monotherapy resulted in an independent centrally confirmed objective response rate (ORR) of 35.5% and a disease control rate of 82%. With a median follow-up of 15.4 months, responses were durable, with a median duration of response of 7.5 (95% confidence interval [CI], 5.7−14.5) months. Median progression-free survival (PFS) was 6.9 (95% CI, 6.2–9.6) months. 6 Downloaded from cancerdiscovery.aacrjournals.org on September 30, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on November 20, 2020; DOI: 10.1158/2159-8290.CD-20-0766 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. There is significant molecular diversity of FGFR2 fusions and rearrangements in
Load more

Recommended publications
  • Effects of Rapamycin on Social Interaction Deficits and Gene
    Kotajima-Murakami et al. Molecular Brain (2019) 12:3 https://doi.org/10.1186/s13041-018-0423-2 RESEARCH Open Access Effects of rapamycin on social interaction deficits and gene expression in mice exposed to valproic acid in utero Hiroko Kotajima-Murakami1,2, Toshiyuki Kobayashi3, Hirofumi Kashii1,4, Atsushi Sato1,5, Yoko Hagino1, Miho Tanaka1,6, Yasumasa Nishito7, Yukio Takamatsu7, Shigeo Uchino1,2 and Kazutaka Ikeda1* Abstract The mammalian target of rapamycin (mTOR) signaling pathway plays a crucial role in cell metabolism, growth, and proliferation. The overactivation of mTOR has been implicated in the pathogenesis of syndromic autism spectrum disorder (ASD), such as tuberous sclerosis complex (TSC). Treatment with the mTOR inhibitor rapamycin improved social interaction deficits in mouse models of TSC. Prenatal exposure to valproic acid (VPA) increases the incidence of ASD. Rodent pups that are exposed to VPA in utero have been used as an animal model of ASD. Activation of the mTOR signaling pathway was recently observed in rodents that were exposed to VPA in utero, and rapamycin ameliorated social interaction deficits. The present study investigated the effect of rapamycin on social interaction deficits in both adolescence and adulthood, and gene expressions in mice that were exposed to VPA in utero. We subcutaneously injected 600 mg/kg VPA in pregnant mice on gestational day 12.5 and used the pups as a model of ASD. The pups were intraperitoneally injected with rapamycin or an equal volume of vehicle once daily for 2 consecutive days. The social interaction test was conducted in the offspring after the last rapamycin administration at 5–6 weeks of ages (adolescence) or 10–11 weeks of age (adulthood).
    [Show full text]
  • Downloaded Using the R Package Cgdsr [40] and Were Used
    Cai et al. BMC Medical Genomics (2020) 13:33 https://doi.org/10.1186/s12920-020-0695-0 RESEARCH ARTICLE Open Access Specific chromatin landscapes and transcription factors couple breast cancer subtype with metastatic relapse to lung or brain Wesley L. Cai1, Celeste B. Greer1,2, Jocelyn F. Chen1, Anna Arnal-Estapé1,3, Jian Cao1,3,4, Qin Yan1,3,5,6*† and Don X. Nguyen1,3,5,6,7*† Abstract Background: Few somatic mutations have been linked to breast cancer metastasis, whereas transcriptomic differences among primary tumors correlate with incidence of metastasis, especially to the lungs and brain. However, the epigenomic alterations and transcription factors (TFs) which underlie these alterations remain unclear. Methods: To identify these, we performed RNA-seq, Chromatin Immunoprecipitation and sequencing (ChIP-seq) and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) of the MDA-MB-231 cell line and its brain (BrM2) and lung (LM2) metastatic sub-populations. We incorporated ATAC-seq data from TCGA to assess metastatic open chromatin signatures, and gene expression data from human metastatic datasets to nominate transcription factor biomarkers. Results: Our integrated epigenomic analyses found that lung and brain metastatic cells exhibit both shared and distinctive signatures of active chromatin. Notably, metastatic sub-populations exhibit increased activation of both promoters and enhancers. We also integrated these data with chromosome conformation capture coupled with ChIP-seq (HiChIP) derived enhancer-promoter interactions to predict enhancer-controlled pathway alterations. We found that enhancer changes are associated with endothelial cell migration in LM2, and negative regulation of epithelial cell proliferation in BrM2. Promoter changes are associated with vasculature development in LM2 and homophilic cell adhesion in BrM2.
    [Show full text]
  • Supplemental Information
    Supplemental information Dissection of the genomic structure of the miR-183/96/182 gene. Previously, we showed that the miR-183/96/182 cluster is an intergenic miRNA cluster, located in a ~60-kb interval between the genes encoding nuclear respiratory factor-1 (Nrf1) and ubiquitin-conjugating enzyme E2H (Ube2h) on mouse chr6qA3.3 (1). To start to uncover the genomic structure of the miR- 183/96/182 gene, we first studied genomic features around miR-183/96/182 in the UCSC genome browser (http://genome.UCSC.edu/), and identified two CpG islands 3.4-6.5 kb 5’ of pre-miR-183, the most 5’ miRNA of the cluster (Fig. 1A; Fig. S1 and Seq. S1). A cDNA clone, AK044220, located at 3.2-4.6 kb 5’ to pre-miR-183, encompasses the second CpG island (Fig. 1A; Fig. S1). We hypothesized that this cDNA clone was derived from 5’ exon(s) of the primary transcript of the miR-183/96/182 gene, as CpG islands are often associated with promoters (2). Supporting this hypothesis, multiple expressed sequences detected by gene-trap clones, including clone D016D06 (3, 4), were co-localized with the cDNA clone AK044220 (Fig. 1A; Fig. S1). Clone D016D06, deposited by the German GeneTrap Consortium (GGTC) (http://tikus.gsf.de) (3, 4), was derived from insertion of a retroviral construct, rFlpROSAβgeo in 129S2 ES cells (Fig. 1A and C). The rFlpROSAβgeo construct carries a promoterless reporter gene, the β−geo cassette - an in-frame fusion of the β-galactosidase and neomycin resistance (Neor) gene (5), with a splicing acceptor (SA) immediately upstream, and a polyA signal downstream of the β−geo cassette (Fig.
    [Show full text]
  • A Mode of Cell Adhesion and Migration Facilitated by CD44-Dependent Microtentacles
    A mode of cell adhesion and migration facilitated by CD44-dependent microtentacles Kayla J. Wolfa,b, Poojan Shuklab, Kelsey Springerb, Stacey Leea,b, Jason D. Coombesb,c, Caleb J. Choyd, Samuel J. Kennye,KeXue,f, and Sanjay Kumara,b,g,1 aUniversity of California, Berkeley–University of California San Francisco Graduate Program in Bioengineering, Department of Bioengineering, University of California, Berkeley, CA 94720; bDepartment of Bioengineering, University of California, Berkeley, CA, 94720; cInflammation Biology, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College London, London, United Kingdom, SE5 9NU; dDepartment of Molecular and Cell Biology, University of California, Berkeley, CA 94720; eDepartment of Chemistry, University of California, Berkeley, CA 94720; fDivision of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720; and gDepartment of Chemical and Biomolecular Engineering, University of California, Berkeley, CA 94720 Edited by David A. Weitz, Harvard University, Cambridge, MA, and approved March 25, 2020 (received for review August 19, 2019) The structure and mechanics of many connective tissues are grafted C6 gliomas (14). Furthermore, knockdown (KD) of dictated by a collagen-rich extracellular matrix (ECM), where col- CD44 in human GBM tumors slows tumor growth and sensitizes lagen fibers provide topological cues that direct cell migration. tumors to cytotoxic agents (15). CD44 is also a marker of glioma However, comparatively little is known about how cells navigate stem cells (GSCs) (also known as tumor-initiating cells) and the hyaluronic acid (HA)-rich, nanoporous ECM of the brain, a contributes to maintaining stemness (16). Our laboratory has problem with fundamental implications for development, inflam- shown that CD44 is necessary for adhesion and migration on mation, and tumor invasion.
    [Show full text]
  • Identification of Differentially Expressed Genes in Human Bladder Cancer Through Genome-Wide Gene Expression Profiling
    521-531 24/7/06 18:28 Page 521 ONCOLOGY REPORTS 16: 521-531, 2006 521 Identification of differentially expressed genes in human bladder cancer through genome-wide gene expression profiling KAZUMORI KAWAKAMI1,3, HIDEKI ENOKIDA1, TOKUSHI TACHIWADA1, TAKENARI GOTANDA1, KENGO TSUNEYOSHI1, HIROYUKI KUBO1, KENRYU NISHIYAMA1, MASAKI TAKIGUCHI2, MASAYUKI NAKAGAWA1 and NAOHIKO SEKI3 1Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520; Departments of 2Biochemistry and Genetics, and 3Functional Genomics, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan Received February 15, 2006; Accepted April 27, 2006 Abstract. Large-scale gene expression profiling is an effective CKS2 gene not only as a potential biomarker for diagnosing, strategy for understanding the progression of bladder cancer but also for staging human BC. This is the first report (BC). The aim of this study was to identify genes that are demonstrating that CKS2 expression is strongly correlated expressed differently in the course of BC progression and to with the progression of human BC. establish new biomarkers for BC. Specimens from 21 patients with pathologically confirmed superficial (n=10) or Introduction invasive (n=11) BC and 4 normal bladder samples were studied; samples from 14 of the 21 BC samples were subjected Bladder cancer (BC) is among the 5 most common to microarray analysis. The validity of the microarray results malignancies worldwide, and the 2nd most common tumor of was verified by real-time RT-PCR. Of the 136 up-regulated the genitourinary tract and the 2nd most common cause of genes we detected, 21 were present in all 14 BCs examined death in patients with cancer of the urinary tract (1-7).
    [Show full text]
  • Differential Gene Expression Profiling of Dystrophic Dog
    Differential Gene Expression Profiling of Dystrophic Dog Muscle after MuStem Cell Transplantation Florence Robriquet, Aurélie Lardenois, Candice Babarit, Thibaut Larcher, Laurence Dubreil, Isabelle Leroux, Céline Zuber, Mireille Ledevin, Jack-Yves Deschamps, Yves Fromes, et al. To cite this version: Florence Robriquet, Aurélie Lardenois, Candice Babarit, Thibaut Larcher, Laurence Dubreil, et al.. Differential Gene Expression Profiling of Dystrophic Dog Muscle after MuStem Cell Transplantation. PLoS ONE, Public Library of Science, 2015, 10 (5), 10.1371/journal.pone.0123336. hal-01222898 HAL Id: hal-01222898 https://hal.archives-ouvertes.fr/hal-01222898 Submitted on 30 Oct 2015 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Distributed under a Creative Commons Attribution| 4.0 International License RESEARCH ARTICLE Differential Gene Expression Profiling of Dystrophic Dog Muscle after MuStem Cell Transplantation Florence Robriquet1,2,3☯, Aurélie Lardenois1,2☯, Candice Babarit1,2, Thibaut Larcher1,2, Laurence Dubreil1,2, Isabelle Leroux1,2, Céline Zuber1,2, Mireille Ledevin1,2, Jack- Yves Deschamps1,2, Yves Fromes2,4, Yan Cherel1,2, Laetitia Guevel1,2,3‡*, Karl Rouger1,2‡ 1 INRA, UMR703 PAnTher, Nantes, France, 2 LUNAM Université, Oniris, École nationale vétérinaire, agro- alimentaire et de l’alimentation Nantes-Atlantique, Nantes, France, 3 Université de Nantes, Nantes, France, 4 Laboratoire RMN AIM-CEA, Institut de Myologie, Hôpital Pitié-Salpêtrière, Paris, France ☯ These authors contributed equally to this work.
    [Show full text]
  • NRBF2 Regulates Autophagy and Prevents Liver Injury by Modulating Atg14l-Linked Phosphatidylinositol-3 Kinase III Activity
    ARTICLE Received 25 Mar 2014 | Accepted 17 Apr 2014 | Published 22 May 2014 DOI: 10.1038/ncomms4920 NRBF2 regulates autophagy and prevents liver injury by modulating Atg14L-linked phosphatidylinositol-3 kinase III activity Jiahong Lu1,2,*, Liqiang He1,*, Christian Behrends3, Masatake Araki4, Kimi Araki5, Qing Jun Wang6, Joseph M. Catanzaro7, Scott L. Friedman8, Wei-Xing Zong7, M. Isabel Fiel9, Min Li2 & Zhenyu Yue1 The Beclin 1-Vps34 complex, the core component of the class III phosphatidylinositol-3 kinase (PI3K-III), binds Atg14L or UVRAG to control different steps of autophagy. However, the mechanism underlying the control of PI3K-III activity remains elusive. Here we report the identification of NRBF2 as a component in the specific PI3K-III complex and a modulator of PI3K-III activity. Through its microtubule interaction and trafficking (MIT) domain, NRBF2 binds Atg14L directly and enhances Atg14L-linked Vps34 kinase activity and autophagy induction. NRBF2-deficient cells exhibit enhanced vulnerability to endoplasmic reticulum (ER) stress that is reversed by re-introducing exogenous NRBF2. NRBF2-deficient mice develop focal liver necrosis and ductular reaction, accompanied by impaired Atg14L-linked Vps34 activity and autophagy, although the mice show no increased mortality. Our data reveal a key role for NRBF2 in the assembly of the specific Atg14L-Beclin 1-Vps34-Vps15 complex for autophagy induction. Thus, NRBF2 modulates autophagy via regulation of PI3K-III and pre- vents ER stress-mediated cytotoxicity and liver injury. 1 Department of Neurology and Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA. 2 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
    [Show full text]
  • A High Throughput, Functional Screen of Human Body Mass Index GWAS Loci Using Tissue-Specific Rnai Drosophila Melanogaster Crosses Thomas J
    Washington University School of Medicine Digital Commons@Becker Open Access Publications 2018 A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J. Baranski Washington University School of Medicine in St. Louis Aldi T. Kraja Washington University School of Medicine in St. Louis Jill L. Fink Washington University School of Medicine in St. Louis Mary Feitosa Washington University School of Medicine in St. Louis Petra A. Lenzini Washington University School of Medicine in St. Louis See next page for additional authors Follow this and additional works at: https://digitalcommons.wustl.edu/open_access_pubs Recommended Citation Baranski, Thomas J.; Kraja, Aldi T.; Fink, Jill L.; Feitosa, Mary; Lenzini, Petra A.; Borecki, Ingrid B.; Liu, Ching-Ti; Cupples, L. Adrienne; North, Kari E.; and Province, Michael A., ,"A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses." PLoS Genetics.14,4. e1007222. (2018). https://digitalcommons.wustl.edu/open_access_pubs/6820 This Open Access Publication is brought to you for free and open access by Digital Commons@Becker. It has been accepted for inclusion in Open Access Publications by an authorized administrator of Digital Commons@Becker. For more information, please contact [email protected]. Authors Thomas J. Baranski, Aldi T. Kraja, Jill L. Fink, Mary Feitosa, Petra A. Lenzini, Ingrid B. Borecki, Ching-Ti Liu, L. Adrienne Cupples, Kari E. North, and Michael A. Province This open access publication is available at Digital Commons@Becker: https://digitalcommons.wustl.edu/open_access_pubs/6820 RESEARCH ARTICLE A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J.
    [Show full text]
  • NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer
    Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 11-7-2018 Decipher Mechanisms by which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer Jairo Ramos [email protected] Follow this and additional works at: https://digitalcommons.fiu.edu/etd Part of the Clinical Epidemiology Commons Recommended Citation Ramos, Jairo, "Decipher Mechanisms by which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer" (2018). FIU Electronic Theses and Dissertations. 3872. https://digitalcommons.fiu.edu/etd/3872 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida DECIPHER MECHANISMS BY WHICH NUCLEAR RESPIRATORY FACTOR ONE (NRF1) COORDINATES CHANGES IN THE TRANSCRIPTIONAL AND CHROMATIN LANDSCAPE AFFECTING DEVELOPMENT AND PROGRESSION OF INVASIVE BREAST CANCER A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in PUBLIC HEALTH by Jairo Ramos 2018 To: Dean Tomás R. Guilarte Robert Stempel College of Public Health and Social Work This dissertation, Written by Jairo Ramos, and entitled Decipher Mechanisms by Which Nuclear Respiratory Factor One (NRF1) Coordinates Changes in the Transcriptional and Chromatin Landscape Affecting Development and Progression of Invasive Breast Cancer, having been approved in respect to style and intellectual content, is referred to you for judgment.
    [Show full text]
  • The Akt-Mtor Pathway Drives Myelin Sheath Growth by Regulating Cap-Dependent Translation
    bioRxiv preprint doi: https://doi.org/10.1101/2021.04.12.439555; this version posted April 12, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC 4.0 International license. Title Page Manuscript Title: The Akt-mTOR pathway drives myelin sheath growth by regulating cap-dependent translation Abbreviated Title: mTOR-mediated translation drives myelination Authors: Karlie N. Fedder-Semmes1,2, Bruce Appel1,3 Affiliations: 1Department of Pediatrics, Section of Developmental Biology 2Neuroscience Graduate Program 3Children’s Hospital Colorado University of Colorado Anschutz Medical Campus Aurora, Colorado, United States of America, 80045 Corresponding author: Bruce Appel, [email protected] Number of pages: 77, including references and figures Number of figures: 8 Acknowledgements: We thank the Appel lab for helpful discussions, Drs. Caleb Doll and Alexandria Hughes for constructive comments on the manuscript, Dr. Katie Yergert for experimental guidance, and Rebecca O’Rourke for help with bioinformatics analysis. This work was supported by US National Institutes of Health (NIH) grant R01 NS095670 and a gift from the Gates Frontiers Fund to B.A. K.N.F-S. was supported by NIH F31 NS115261 and NIH T32 NS099042. The University of Colorado Anschutz Medical Campus Zebrafish Core Facility was supported by NIH grant P30 NS048154. Conflict of Interest: The authors declare no competing financial interests. bioRxiv preprint doi: https://doi.org/10.1101/2021.04.12.439555; this version posted April 12, 2021.
    [Show full text]
  • A High Throughput, Functional Screen of Human Body Mass Index GWAS Loci Using Tissue-Specific Rnai Drosophila Melanogaster Crosses
    RESEARCH ARTICLE A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses Thomas J. Baranski1*, Aldi T. Kraja2, Jill L. Fink1, Mary Feitosa2, Petra A. Lenzini2, Ingrid B. Borecki3, Ching-Ti Liu4, L. Adrienne Cupples4, Kari E. North5, Michael A. Province2* a1111111111 1 Department of Internal Medicine, Division of Endocrinology, Metabolism and Lipid Research, Washington University School of Medicine, St. Louis, Missouri, United States of America, 2 Department of Genetics and a1111111111 Center for Genome Sciences and Systems Biology, Division of Statistical Genomics, Washington University a1111111111 School of Medicine, St. Louis, Missouri, United States of America, 3 Department of Biostatistics, University of a1111111111 Washington, Seattle, Washington, United States of America, 4 Department of Biostatistics, Boston University a1111111111 School of Public Health, Boston, Massachusetts, United States of America, 5 Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, United States of America * [email protected] (TJB); [email protected] (MAP) OPEN ACCESS Citation: Baranski TJ, Kraja AT, Fink JL, Feitosa M, Abstract Lenzini PA, Borecki IB, et al. (2018) A high Human GWAS of obesity have been successful in identifying loci associated with adiposity, throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi but for the most part, these are non-coding SNPs whose function, or even whose gene of Drosophila melanogaster crosses. PLoS Genet 14 action, is unknown. To help identify the genes on which these human BMI loci may be oper- (4): e1007222. https://doi.org/10.1371/journal. ating, we conducted a high throughput screen in Drosophila melanogaster.
    [Show full text]
  • Pkcε Switches Aurora B Specificity to Exit the Abscission Checkpoint
    ARTICLE Received 4 Jan 2016 | Accepted 3 Nov 2016 | Published 22 Dec 2016 DOI: 10.1038/ncomms13853 OPEN PKCe switches Aurora B specificity to exit the abscission checkpoint Tanya Pike1, Nicola Brownlow1,w, Svend Kjaer2, Jeremy Carlton3 & Peter J. Parker1,3 The ‘NoCut’, or Aurora B abscission checkpoint can be activated if DNA is retained in the cleavage furrow after completion of anaphase. Checkpoint failure leads to incomplete abscission and a binucleate outcome. These phenotypes are also observed after loss of PKCe in transformed cell models. Here we show that PKCe directly modulates the Aurora B-dependent abscission checkpoint by phosphorylating Aurora B at S227. This phosphorylation invokes a switch in Aurora B specificity, with increased phosphorylation of a subset of target substrates, including the CPC subunit Borealin. This switch is essential for abscission checkpoint exit. Preventing the phosphorylation of Borealin leads to abscission failure, as does expression of a non-phosphorylatable Aurora B S227A mutant. Further, depletion of the ESCRT-III component and Aurora B substrate CHMP4C enables abscission, bypassing the PKCe–Aurora B exit pathway. Thus, we demonstrate that PKCe signals through Aurora B to exit the abscission checkpoint and complete cell division. 1 Protein Phosphorylation Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. 2 Protein Purification Facility, Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK. 3 Division of Cancer Studies King’s College London, New Hunt’s House, Guy’s Campus, London SE1 1UL, UK. w Present address: Centre for Genomic Regulation (CRG), Dr Aiguader, 88, PRBB Building, 08003 Barcelona, Spain.
    [Show full text]