DOCSLIB.ORG

Integration of Genomic and Transcriptomic Markers Improves The

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Integration of Genomic and Transcriptomic Markers Improves The Author Manuscript Published OnlineFirst on April 23, 2021; DOI: 10.1158/1078-0432.CCR-20-4375 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Integration of genomic and transcriptomic markers improves the 2 prognosis prediction of acute promyelocytic leukemia 3 4 Authors and Affiliations: 5 Xiaojing Lin1, Niu Qiao1, Yang Shen1, Hai Fang1, Qing Xue1, Bowen Cui1, Li Chen1, Hongming 6 Zhu1, Sujiang Zhang1, Yu Chen1, Lu Jiang1, Shengyue Wang1, Junmin Li1, Bingshun Wang2, 7 Bing Chen1, Zhu Chen1, Saijuan Chen1, 8 L.X.J., Q.N., S.Y. contributed equally to this work. 9 1Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National 10 Research Center for Translational Medicine (Shanghai), Rui-Jin Hospital, Shanghai Jiao Tong 11 University School of Medicine and School of Life Sciences and Biotechnology, Shanghai Jiao 12 Tong University, 200025, Shanghai, China 13 2Department of Biostatistics and Clinical Research Center, Shanghai Jiao Tong University 14 School of Medicine, 200025, Shanghai, China 15 16 Running head: Integrated genomic and transcriptomic model in APL 17 Keywords: APL, NRAS, genomics, transcriptomics, prognosis 18 Corresponding authors: 19 Saijuan Chen, State Key Laboratory of Medical Genomics, Shanghai Institute of Hematology, 20 National Research Center for Translational Medicine (Shanghai), Rui-Jin Hospital, Shanghai 21 Jiao Tong University School of Medicine and School of Life Sciences and Biotechnology, 22 Shanghai Jiao Tong University,197 Rui-Jin Er Road, 23 Shanghai, 200025,China 24 Tel: +86-21-33562658 25 Fax: +86-21-64743206 26 E-mail: [email protected] 27 28 29 Zhu Chen, MD, PhD 30 Shanghai Institute of Hematology, 31 Rui-Jin Hospital, 1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2021; DOI: 10.1158/1078-0432.CCR-20-4375 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 197 Rui-Jin Er Road, 2 Shanghai 200025,China 3 Tel: +86-21-33562658 4 Fax: +86-21-64743206 5 E-mail: [email protected] 6 7 Yang Shen, MD, PhD 8 Shanghai Institute of Hematology, 9 Rui-Jin Hospital, 10 197 Rui-Jin Er Road, 11 Shanghai 200025,China 12 Tel: +86-21-33562658 13 Fax: +86-21-64743206 14 E-mail: [email protected] 15 16 17 Competing interests 18 All authors declare no competing interest. 19 2 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2021; DOI: 10.1158/1078-0432.CCR-20-4375 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Statement of translational relevance 2 Acute promyeloid leukemia (APL), which is used to be one of the deadliest forms of cancer, 3 has gradually become highly curable. However, in a subset of APL patients, early death and 4 relapse remained challenges for the treatment. Moreover, with the treatment strategy evolved 5 from ATRA and chemotherapy (ATRA–chemotherapy)- to ATRA and ATO (ATRA–ATO)-based 6 synergistic targeted therapy, the classic risk stratification needs further improvement. In this 7 study, we identified a feasible and reliable way and established an integrated system to 8 discriminate APL patients into high- (HR) and standard-risk (SR) groups. The revised HR 9 group displayed significantly worse outcomes than the revised SR one. In summary, we could 10 better define the risks of APL, add predictive value to the choice of currently available 11 therapeutic tools, and make the clinical decision more convenient and clearer. 12 3 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2021; DOI: 10.1158/1078-0432.CCR-20-4375 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Abstract 2 Purpose: The current stratification system for acute promyelocytic leukemia (APL) is based on 3 the white blood cell (WBC) and the platelet counts (i.e., Sanz score) over the past two decades. 4 However, the borderlines among different risk groups are sometimes ambiguous, and for some 5 patients, early death and relapse remained challenges. Besides, with the evolving of the 6 treatment strategy from ATRA-chemotherapy to ATRA-ATO-based synergistic targeted therapy, 7 the precise risk stratification with molecular markers is needed. 8 Patients and Methods: This study performed a systematic analysis of APL genomics and 9 transcriptomics to identify genetic abnormalities in 348 patients mainly from the APL2012 trial 10 (NCT01987297) to illustrate the potential molecular background of Sanz score and further 11 optimize it. The least absolute shrinkage and selection operator (LASSO) algorithm was used 12 to analyze the gene expression in 323 cases to establish a scoring system (i.e., APL9 score). 13 Results: Through combining NRAS mutations, APL9 score with WBC, 321 cases can be 14 stratified into two groups with significantly different outcomes. The estimated 5-year overall (P 15 = 0.00031), event-free (P < 0.0001), and disease-free (P = 0.001) survival rates in the revised 16 standard-risk group (95.6%, 93.8%, and 98.1%, respectively) were significantly better than 17 those in the revised high-risk group (82.9%, 77.4%, and 88.4%, respectively), which could be 18 validated using The Cancer Genome Atlas dataset. 19 Conclusions: We have proposed a two-category system improving prognosis in APL patients. 20 Molecular markers identified in this study may also provide genomic insights into the disease 21 mechanism for improved therapy. 22 4 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2021; DOI: 10.1158/1078-0432.CCR-20-4375 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Introduction 2 Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML), 3 characterized by the expansion and accumulation of leukemic cells blocked at the 4 promyelocytic stage of granulocytic differentiation and the presence of a specific disease driver 5 fusion gene encoding the PML–RARA oncoprotein. In the last two decades, the 6 all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO)-based combination (ATRA–ATO) 7 showed a considerable advantage over traditional ATRA and chemotherapy combination 8 (ATRA–chemotherapy)-based protocol and has become the standard APL core treatment 9 regimen nowadays (1-3). Meanwhile, the Sanz score was widely used to classify APL patients 10 into three risk categories according to white blood cell (WBC) and platelet (PLT) counts 11 (low-risk: WBC count ≤ 10 × 109/L and PLT count > 40 × 109/L; intermediate-risk: WBC count 12 ≤ 10 × 109/L and PLT count ≤ 40 × 109/L; and high-risk: WBC count >10 × 109/L) (4). 13 While Sanz score represents a very useful first-generation tool to stratify APL, we propose to 14 further enrich the current APL risk evaluation system taking into consideration several factors. 15 First, although the hemogram criteria of the risks of APL seem to be easily applicable, such 16 criteria appear not so straightforward for some patients, especially due to the fluctuation in 17 WBC and PLT levels caused by infection and drugs. Notably, now ATRA is routinely used to 18 treat APL, often causing leukocytosis syndrome (5). The inclusion of reliable molecular 19 markers can be of great value in this aspect. Second, the data to generate the Sanz risk score 20 was mostly from the clinical trials of ATRA–chemotherapy, which showed significant inferior 21 results as compared to current ATRA–ATO treatment in low- and intermediate-risk categories 22 (6). Third, the identification of biological markers related to distinct disease outcomes may 23 allow not only a better understanding of the molecular mechanisms underlying different clinical 24 phenotypes as those in Sanz score but also a precision use of novel therapeutic methods, 25 such as targeted drugs or immune therapies. 26 Therefore, we generated gene mutations and expression profiles of 348 APL patients enrolled 27 in the APL2012 trial (NCT01987297), the largest cohort ever reported(7). Integration of 28 genomics and transcriptomics allowed us to panoramically clarify the importance of gene 29 mutations and expression profiles on the risk assessment and the prognosis of APL. 5 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2021 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 23, 2021; DOI: 10.1158/1078-0432.CCR-20-4375 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 1 Patients and Methods 2 Patients 3 A total of 348 APL patients with available bone marrow (BM) samples were included in this 4 study, including a majority part of the patients (n = 304) coming from the APL2012 clinical trial 5 (NCT01987297) from December 6, 2012 to December 31, 2017, and a small group of the 6 patients (n = 44) from the historical cases between June 1, 2012 to November 31, 2012, who 7 received the similar treatment (Table 1). It is noteworthy that the key part in APL2012 trial for 8 randomization into two groups with or without ATO was at the phase of consolidation while all 9 patients received ATRA–ATO treatment for remission induction and maintenance. As a result, 10 there were no statistically significant differences in terms of 3-year disease-free survival (DFS) 11 as well as estimated 7-year DFS and overall survival (OS) between the two groups(7). When 12 the 348 cases investigated in the present work were scrutinized for their treatment and 13 outcome data, there were 22 cases of early death during remission induction and two cases 14 who were lost during follow-up.
Load more

Recommended publications
  • The HECT Domain Ubiquitin Ligase HUWE1 Targets Unassembled Soluble Proteins for Degradation
    OPEN Citation: Cell Discovery (2016) 2, 16040; doi:10.1038/celldisc.2016.40 ARTICLE www.nature.com/celldisc The HECT domain ubiquitin ligase HUWE1 targets unassembled soluble proteins for degradation Yue Xu1, D Eric Anderson2, Yihong Ye1 1Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; 2Advanced Mass Spectrometry Core Facility, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA In eukaryotes, many proteins function in multi-subunit complexes that require proper assembly. To maintain complex stoichiometry, cells use the endoplasmic reticulum-associated degradation system to degrade unassembled membrane subunits, but how unassembled soluble proteins are eliminated is undefined. Here we show that degradation of unassembled soluble proteins (referred to as unassembled soluble protein degradation, USPD) requires the ubiquitin selective chaperone p97, its co-factor nuclear protein localization protein 4 (Npl4), and the proteasome. At the ubiquitin ligase level, the previously identified protein quality control ligase UBR1 (ubiquitin protein ligase E3 component n-recognin 1) and the related enzymes only process a subset of unassembled soluble proteins. We identify the homologous to the E6-AP carboxyl terminus (homologous to the E6-AP carboxyl terminus) domain-containing protein HUWE1 as a ubiquitin ligase for substrates bearing unshielded, hydrophobic segments. We used a stable isotope labeling with amino acids-based proteomic approach to identify endogenous HUWE1 substrates. Interestingly, many HUWE1 substrates form multi-protein com- plexes that function in the nucleus although HUWE1 itself is cytoplasmically localized. Inhibition of nuclear entry enhances HUWE1-mediated ubiquitination and degradation, suggesting that USPD occurs primarily in the cytoplasm.
    [Show full text]
  • The Results of an X-Chromosome Exome Sequencing Study
    Open Access Research BMJ Open: first published as 10.1136/bmjopen-2015-009537 on 29 April 2016. Downloaded from HUWE1 mutations in Juberg-Marsidi and Brooks syndromes: the results of an X-chromosome exome sequencing study Michael J Friez,1 Susan Sklower Brooks,2 Roger E Stevenson,1 Michael Field,3 Monica J Basehore,1 Lesley C Adès,4 Courtney Sebold,5 Stephen McGee,1 Samantha Saxon,1 Cindy Skinner,1 Maria E Craig,4 Lucy Murray,3 Richard J Simensen,1 Ying Yzu Yap,6 Marie A Shaw,6 Alison Gardner,6 Mark Corbett,6 Raman Kumar,6 Matthias Bosshard,7 Barbara van Loon,7 Patrick S Tarpey,8 Fatima Abidi,1 Jozef Gecz,6 Charles E Schwartz1 To cite: Friez MJ, Brooks SS, ABSTRACT et al Strengths and limitations of this study Stevenson RE, . HUWE1 Background: X linked intellectual disability (XLID) mutations in Juberg-Marsidi syndromes account for a substantial number of males ▪ and Brooks syndromes: the Using the power of next generation sequencing, with ID. Much progress has been made in identifying results of an X-chromosome we have linked Juberg-Marsidi syndrome ( JMS) exome sequencing study. the genetic cause in many of the syndromes described and Brooks syndrome as allelic conditions. – BMJ Open 2016;6:e009537. 20 40 years ago. Next generation sequencing (NGS) ▪ This study provides better organisation to the doi:10.1136/bmjopen-2015- has contributed to the rapid discovery of XLID genes field of X linked disorders by providing evidence 009537 and identifying novel mutations in known XLID genes that JMS is not caused by mutation in the ATRX for many of these syndromes.
    [Show full text]
  • The Inactive X Chromosome Is Epigenetically Unstable and Transcriptionally Labile in Breast Cancer
    Supplemental Information The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer Ronan Chaligné1,2,3,8, Tatiana Popova1,4, Marco-Antonio Mendoza-Parra5, Mohamed-Ashick M. Saleem5 , David Gentien1,6, Kristen Ban1,2,3,8, Tristan Piolot1,7, Olivier Leroy1,7, Odette Mariani6, Hinrich Gronemeyer*5, Anne Vincent-Salomon*1,4,6,8, Marc-Henri Stern*1,4,6 and Edith Heard*1,2,3,8 Extended Experimental Procedures Cell Culture Human Mammary Epithelial Cells (HMEC, Invitrogen) were grown in serum-free medium (HuMEC, Invitrogen). WI- 38, ZR-75-1, SK-BR-3 and MDA-MB-436 cells were grown in Dulbecco’s modified Eagle’s medium (DMEM; Invitrogen) containing 10% fetal bovine serum (FBS). DNA Methylation analysis. We bisulfite-treated 2 µg of genomic DNA using Epitect bisulfite kit (Qiagen). Bisulfite converted DNA was amplified with bisulfite primers listed in Table S3. All primers incorporated a T7 promoter tag, and PCR conditions are available upon request. We analyzed PCR products by MALDI-TOF mass spectrometry after in vitro transcription and specific cleavage (EpiTYPER by Sequenom®). For each amplicon, we analyzed two independent DNA samples and several CG sites in the CpG Island. Design of primers and selection of best promoter region to assess (approx. 500 bp) were done by a combination of UCSC Genome Browser (http://genome.ucsc.edu) and MethPrimer (http://www.urogene.org). All the primers used are listed (Table S3). NB: MAGEC2 CpG analysis have been done with a combination of two CpG island identified in the gene core. Analysis of RNA allelic expression profiles (based on Human SNP Array 6.0) DNA and RNA hybridizations were normalized by Genotyping console.
    [Show full text]
  • A Upf3b-Mutant Mouse Model with Behavioral and Neurogenesis Defects
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Mol Psychiatry Manuscript Author . Author Manuscript Author manuscript; available in PMC 2018 September 27. Published in final edited form as: Mol Psychiatry. 2018 August ; 23(8): 1773–1786. doi:10.1038/mp.2017.173. A Upf3b-mutant mouse model with behavioral and neurogenesis defects L Huang1, EY Shum1, SH Jones1, C-H Lou1, J Dumdie1, H Kim1, AJ Roberts2, LA Jolly3,4, J Espinoza1, DM Skarbrevik1, MH Phan1, H Cook-Andersen1, NR Swerdlow5, J Gecz3,4, and MF Wilkinson1,6 1Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, California, USA 2Department of Molecular and Cellular Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road, MB6, La Jolla, CA 92037, USA 3School Adelaide Medical School and Robison Research Institute, University of Adelaide, Adelaide, SA 5005, Australia 4South Australian Health and Medical Research Institute, Adelaide, SA, 5005, Australia 5Department of Psychiatry, School of Medicine, University of California, San Diego, La Jolla, California, USA 6Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA Abstract Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia (SCZ).
    [Show full text]
  • DNA Damage-Induced Histone H1 Ubiquitylation Is Mediated by HUWE1 and Stimulates the RNF8-RNF168 Pathway
    www.nature.com/scientificreports OPEN DNA damage-induced histone H1 ubiquitylation is mediated by HUWE1 and stimulates the RNF8- Received: 27 April 2017 Accepted: 16 October 2017 RNF168 pathway Published: xx xx xxxx I. K. Mandemaker1, L. van Cuijk1, R. C. Janssens1, H. Lans 1, K. Bezstarosti2, J. H. Hoeijmakers1, J. A. Demmers2, W. Vermeulen1 & J. A. Marteijn1 The DNA damage response (DDR), comprising distinct repair and signalling pathways, safeguards genomic integrity. Protein ubiquitylation is an important regulatory mechanism of the DDR. To study its role in the UV-induced DDR, we characterized changes in protein ubiquitylation following DNA damage using quantitative di-Gly proteomics. Interestingly, we identifed multiple sites of histone H1 that are ubiquitylated upon UV-damage. We show that UV-dependent histone H1 ubiquitylation at multiple lysines is mediated by the E3-ligase HUWE1. Recently, it was shown that poly-ubiquitylated histone H1 is an important signalling intermediate in the double strand break response. This poly-ubiquitylation is dependent on RNF8 and Ubc13 which extend pre-existing ubiquitin modifcations to K63-linked chains. Here we demonstrate that HUWE1 depleted cells showed reduced recruitment of RNF168 and 53BP1 to sites of DNA damage, two factors downstream of RNF8 mediated histone H1 poly-ubiquitylation, while recruitment of MDC1, which act upstream of histone H1 ubiquitylation, was not afected. Our data show that histone H1 is a prominent target for ubiquitylation after UV-induced DNA damage. Our data are in line with a model in which HUWE1 primes histone H1 with ubiquitin to allow ubiquitin chain elongation by RNF8, thereby stimulating the RNF8-RNF168 mediated DDR.
    [Show full text]
  • Roles of the HUWE1 Ubiquitin Ligase in Nervous System Development, Function and Disease Andrew C
    Giles and Grill Neural Development (2020) 15:6 https://doi.org/10.1186/s13064-020-00143-9 REVIEW Open Access Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease Andrew C. Giles and Brock Grill* Abstract Huwe1 is a highly conserved member of the HECT E3 ubiquitin ligase family. Here, we explore the growing importance of Huwe1 in nervous system development, function and disease. We discuss extensive progress made in deciphering how Huwe1 regulates neural progenitor proliferation and differentiation, cell migration, and axon development. We highlight recent evidence indicating that Huwe1 regulates inhibitory neurotransmission. In covering these topics, we focus on findings made using both vertebrate and invertebrate in vivo model systems. Finally, we discuss extensive human genetic studies that strongly implicate HUWE1 in intellectual disability, and heighten the importance of continuing to unravel how Huwe1 affects the nervous system. Keywords: Huwe1, EEL-1, Ubiquitin ligase, HECT, Neuron, Neural progenitor, Neurotransmission, Axon, Transcription factor, Intellectual disability Introduction evidence implicating Huwe1 in multiple neurodevelop- HECT, UBA and WWE domain containing protein 1 mental disorders, including both non-syndromic and syn- (Huwe1) is an E3 ubiquitin ligase that is highly conserved dromic forms of X-linked intellectual disability (ID). In across the animal kingdom [1–4](Fig.1a). While rodent, this review, we discuss how Huwe1 contributes to nervous zebrafish and fly orthologs are also generally referred to as system development, function and disease. We hope that Huwe1, the C. elegans ortholog is called Enhancer of EFL- exploring this literature encourages further studies on 1 (EEL-1) based on its discovery in genetic screens.
    [Show full text]
  • Assessment of Copy Number Variations in 120 Patients with Poland
    Vaccari et al. BMC Medical Genetics (2016) 17:89 DOI 10.1186/s12881-016-0351-x RESEARCHARTICLE Open Access Assessment of copy number variations in 120 patients with Poland syndrome Carlotta Maria Vaccari1, Elisa Tassano2, Michele Torre3, Stefania Gimelli4, Maria Teresa Divizia2, Maria Victoria Romanini5, Simone Bossi1, Ilaria Musante1, Maura Valle6, Filippo Senes7, Nunzio Catena7, Maria Francesca Bedeschi8, Anwar Baban2,10, Maria Grazia Calevo9, Massimo Acquaviva1, Margherita Lerone2, Roberto Ravazzolo1,2 and Aldamaria Puliti1,2* Abstract Background: Poland Syndrome (PS) is a rare congenital disorder presenting with agenesis/hypoplasia of the pectoralis major muscle variably associated with thoracic and/or upper limb anomalies. Most cases are sporadic, but familial recurrence, with different inheritance patterns, has been observed. The genetic etiology of PS remains unknown. Karyotyping and array-comparative genomic hybridization (CGH) analyses can identify genomic imbalances that can clarify the genetic etiology of congenital and neurodevelopmental disorders. We previously reported a chromosome 11 deletion in twin girls with pectoralis muscle hypoplasia and skeletal anomalies, and a chromosome six deletion in a patient presenting a complex phenotype that included pectoralis muscle hypoplasia. However, the contribution of genomic imbalances to PS remains largely unknown. Methods: To investigate the prevalence of chromosomal imbalances in PS, standard cytogenetic and array-CGH analyses were performed in 120 PS patients. Results: Following the application of stringent filter criteria, 14 rare copy number variations (CNVs) were identified in 14 PS patients in different regions outside known common copy number variations: seven genomic duplications and seven genomic deletions, enclosing the two previously reported PS associated chromosomal deletions. These CNVs ranged from 0.04 to 4.71 Mb in size.
    [Show full text]
  • Shinydepmap, a Tool to Identify Targetable Cancer Genes and Their Functional Connections from Cancer Dependency Map Data
    TOOLS AND RESOURCES shinyDepMap, a tool to identify targetable cancer genes and their functional connections from Cancer Dependency Map data Kenichi Shimada*, John A Bachman, Jeremy L Muhlich, Timothy J Mitchison Laboratory of Systems Pharmacology and Department of Systems Biology, Harvard Medical School, Boston, United States Abstract Individual cancers rely on distinct essential genes for their survival. The Cancer Dependency Map (DepMap) is an ongoing project to uncover these gene dependencies in hundreds of cancer cell lines. To make this drug discovery resource more accessible to the scientific community, we built an easy-to-use browser, shinyDepMap (https://labsyspharm.shinyapps.io/ depmap). shinyDepMap combines CRISPR and shRNA data to determine, for each gene, the growth reduction caused by knockout/knockdown and the selectivity of this effect across cell lines. The tool also clusters genes with similar dependencies, revealing functional relationships. shinyDepMap can be used to (1) predict the efficacy and selectivity of drugs targeting particular genes; (2) identify maximally sensitive cell lines for testing a drug; (3) target hop, that is, navigate from an undruggable protein with the desired selectivity profile, such as an activated oncogene, to more druggable targets with a similar profile; and (4) identify novel pathways driving cancer cell growth and survival. *For correspondence: [email protected]. Introduction edu Cancer is a disease of the genome. Hundreds, if not thousands, of driver mutations cause cancer in different patients (MC3 Working Group et al., 2018), and extensive collaborative efforts such as Competing interest: See the Cancer Genome Atlas Program (TCGA) have helped discover them (The Cancer Genome Atlas page 17 Research Network, 2019).
    [Show full text]
  • Dynamic Changes in Paternal X-Chromosome Activity During Imprinted X-Chromosome Inactivation in Mice
    Dynamic changes in paternal X-chromosome activity during imprinted X-chromosome inactivation in mice Catherine Patrata,b, Ikuhiro Okamotoa, Patricia Diabangouayaa, Vivian Vialonc, Patricia Le Baccond, Jennifer Chowa, and Edith Hearda,1 aMammalian Developmental Epigenetics Group, Institut Curie, Centre National Research Scientifique Unité Mixte de Recherche 3215, Institut Nationaldela Santé et de la Recherche Médicale U934, 75248 Paris, France; bLaboratoire de Biologie de la Reproduction and cMedical Informatics Unit, Université Paris Descartes, Assistance Publique-Hoˆpitaux de Paris, 75014 Paris, France; and dChromatin Dynamics Group, Institut Curie Centre National de la Recherche Scientifique Unite´Mixte de Recherche 218–Nuclear Dynamics and Genome Plasticity, 75248 Paris, France Edited by Mary F. Lyon, Medical Research Council, Didcot, Oxon, United Kingdom, and approved January 22, 2009 (received for review October 23, 2008) In mammals, X-chromosome dosage compensation is achieved by inactivate, the early activity of the paternal genome would result in inactivating one of the two X chromosomes in females. In mice, X paternal Xist activity and trigger subsequent Xp inactivation (12). inactivation is initially imprinted, with inactivation of the paternal Another hypothesis is that the Xp is transmitted to the zygote in a X (Xp) chromosome occurring during preimplantation develop- preinactivated state because of its passage through the male germ ment. One theory is that the Xp is preinactivated in female line (13). Here, the X and Y undergo meiotic sex chromosome embryos, because of its previous silence during meiosis in the male inactivation (MSCI) followed by postmeiotic sex chromatin forma- germ line. The extent to which the Xp is active after fertilization tion (PMSC) (14, 15).
    [Show full text]
  • ALS Mutations of FUS Suppress Protein Translation and Disrupt the Regulation of Nonsense-Mediated Decay
    ALS mutations of FUS suppress protein translation and disrupt the regulation of nonsense-mediated decay Marisa Kamelgarna, Jing Chenb, Lisha Kuangb, Huan Jina, Edward J. Kasarskisa,c, and Haining Zhua,b,d,1 aDepartment of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536; bDepartment of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536; cDepartment of Neurology, College of Medicine, University of Kentucky, Lexington, KY 40536; and dLexington VA Medical Center, Research and Development, Lexington, KY 40502 Edited by Gregory A. Petsko, Weill Cornell Medical College, New York, NY, and approved October 22, 2018 (received for review June 16, 2018) Amyotrophic lateral sclerosis (ALS) is an incurable neurodegener- This study started with testing the hypothesis that the identi- ative disease characterized by preferential motor neuron death. fication of proteins associated with mutant FUS-dependent cy- Approximately 15% of ALS cases are familial, and mutations in the toplasmic granules is likely to provide critical insights into the fused in sarcoma (FUS) gene contribute to a subset of familial ALS toxic mechanism of mutant FUS. We developed a protocol to cases. FUS is a multifunctional protein participating in many RNA capture the dynamic mutant FUS-positive granules (3, 4) by metabolism pathways. ALS-linked mutations cause a liquid–liquid membrane filtration and identified protein components by pro- phase separation of FUS protein in vitro, inducing the formation of teomic approaches. The bioinformatics analysis of proteins cytoplasmic granules and inclusions. However, it remains elusive identified in wild-type (WT) and mutant FUS granules revealed what other proteins are sequestered into the inclusions and how multiple RNA metabolism pathways, among which protein such a process leads to neuronal dysfunction and degeneration.
    [Show full text]
  • Modular HUWE1 Architecture Serves As Hub for Degradation of Cell-Fate Decision Factors
    bioRxiv preprint doi: https://doi.org/10.1101/2020.08.19.257352; this version posted August 19, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder. All rights reserved. No reuse allowed without permission. Modular HUWE1 architecture serves as hub for degradation of cell-fate decision factors Authors: Moritz Hunkeler1,2, Cyrus Y. Jin1,2, Michelle W. Ma1,2, Daan Overwijn1,2, Julie K. Monda3, Eric J. Bennett3, Eric S. Fischer1,2,4,* Affiliations: 1 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA. 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA. 3Division of Biological Sciences, Section of Cell and Developmental Biology, University of California San Diego, La Jolla, CA. 4 Lead contact. *Correspondence to: [email protected] Summary: HECT ubiquitin ligases play essential roles in metazoan development and physiology. The HECT ligase HUWE1 is central to the cellular stress response by mediating degradation of key death or survival factors including Mcl1, p53, DDIT4, and Myc. As a step toward understanding regulation of HUWE1 engagement with its diverse substrates, we present here the cryo-EM structure of HUWE1, offering a first complete molecular picture of a HECT ubiquitin ligase. The ~4400 amino acid residue polypeptide forms an alpha solenoid- shaped assembly with a central pore decorated with protein interaction modules. This modularity enables HUWE1 to target a wide range of substrates for destruction. The locations of human mutations associated with severe neurodevelopmental disorders link functions of this essential enzyme with its three-dimensional organization.
    [Show full text]
  • Pathway Entry Into the T Lymphocyte Developmental Molecular Dissection of Prethymic Progenitor
    The Journal of Immunology Molecular Dissection of Prethymic Progenitor Entry into the T Lymphocyte Developmental Pathway1 C. Chace Tydell,2 Elizabeth-Sharon David-Fung,2,3 Jonathan E. Moore, Lee Rowen,4 Tom Taghon,5 and Ellen V. Rothenberg6 Notch signaling activates T lineage differentiation from hemopoietic progenitors, but relatively few regulators that initiate this program have been identified, e.g., GATA3 and T cell factor-1 (TCF-1) (gene name Tcf7). To identify additional regulators of T cell specification, a cDNA library from mouse Pro-T cells was screened for genes that are specifically up-regulated in intrathymic T cell precursors as compared with myeloid progenitors. Over 90 genes of interest were iden- tified, and 35 of 44 tested were confirmed to be more highly expressed in T lineage precursors relative to precursors of B and/or myeloid lineage. To a remarkable extent, however, expression of these T lineage-enriched genes, including zinc finger transcription factor, helicase, and signaling adaptor genes, was also shared by stem cells (Lin؊Sca-1؉Kit؉CD27؊) and multipotent progenitors (Lin؊Sca-1؉Kit؉CD27؉), although down-regulated in other lineages. Thus, a major fraction of these early T lineage genes are a regulatory legacy from stem cells. The few genes sharply up-regulated between multipotent progenitors and Pro-T cell stages included those encoding transcription factors Bcl11b, TCF-1 (Tcf7), and HEBalt, Notch target Deltex1, Deltex3L, Fkbp5, Eva1, and Tmem131. Like GATA3 and Deltex1, Bcl11b, Fkbp5, and Eva1 were dependent on Notch/Delta signaling for induction in fetal liver precursors, but only Bcl11b and HEBalt were up-regulated between the first two stages of intrathymic T cell development (double negative 1 and double negative 2) corresponding to T lineage specification.
    [Show full text]