DOCSLIB.ORG

A Multicenter, Randomized Study of Decitabine As Epigenetic

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A Multicenter, Randomized Study of Decitabine As Epigenetic Manuscript bioRxiv preprint doi: https://doi.org/10.1101/124263; this version postedClick June here14, 2017. to download The copyright Manuscript holder for this Decitabine preprint (which _ClinicEpigen_4- was not certified by peer review) is the author/funder, who has granted bioRxiv a3-17_CG1_FINAL.docx license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Click here to view linked References 1 2 3 4 5 1 A multicenter, randomized study of decitabine as 6 7 8 2 epigenetic priming with induction chemotherapy in 9 10 11 3 children with AML 12 13 14 4 15 5 Lia Gore,1 Timothy J. Triche, Jr.,2 Jason E. Farrar,3 Daniel Wai,4 Christophe Legendre,5 16 17 6 Gerald C Gooden,2,5 Winnie S. Liang,5 John Carpten,5 David Lee,6 Frank Alvaro,7 18 19 1 8 9 10 11 20 7 Margaret E. Macy, Carola Arndt, Philip Barnette, Todd Cooper, Laura Martin, Aru 21 22 8 Narendran,12 Jessica Pollard,13 Soheil Meshinchi,14 Jessica Boklan,15 Robert J 23 24 9 Arceci*,4,6,15 and Bodour Salhia*,2,5 25 26 10 27 11 28 12 Children’s Hospital Colorado and University of Colorado School of Medicine, Aurora CO1; Jane 29 13 Anne Nohl Division of Hematology, Keck Medicine of USC and Norris Comprehensive Cancer 30 14 Center, Los Angeles, CA2; Arkansas Children’s Research Institute and University of Arkansas for 31 15 Medical Sciences, Little Rock, AR3; Ron Matricaria Institute of Molecular Medicine, Phoenix, AZ4; 32 16 Translational Genomics Research Institute, Phoenix, AZ5; Sidney Kimmel Comprehensive 33 17 Cancer Center at Johns Hopkins’ University, Baltimore MD6; John Hunter Hospital, New South 34 18 Wales, Australia7; Mayo Clinic, Rochester MN8; Primary Children’s Medical Center and the 35 19 University of Utah, Salt Lake City UT9; Children’s Healthcare of Atlanta, Atlanta GA10; Nationwide 36 20 Children’s Hospital, Columbus OH11; Alberta Children’s Hospital and University of Calgary, 37 21 Calgary, AB, Canada12; Seattle Children’s Hospital13 Seattle, WA and Fred Hutchinson Cancer 38 22 Research Center14, Seattle WA; Phoenix Children’s Hospital, Phoenix, AZ15 39 23 40 24 41 [email protected], [email protected], 42 25 [email protected], [email protected], 43 26 [email protected], [email protected], [email protected], [email protected], 44 27 [email protected], [email protected], 45 28 [email protected], [email protected], [email protected], 46 29 [email protected], [email protected], [email protected], 47 30 [email protected], [email protected], [email protected], [email protected], 48 31 [email protected] 49 32 50 33 *These authors contributed equally to this work. 51 34 52 35 Corresponding Author: Lia Gore, MD 53 36 Center for Cancer and Blood Disorders 54 37 Children’s Hospital Colorado 55 38 13123 East 16th Av, Box B115 56 57 39 Aurora CO 80045 58 40 Tel: 720-777-6458 59 41 Fax: 720-777-7339 60 42 [email protected] 61 62 1 63 64 65 bioRxiv preprint doi: https://doi.org/10.1101/124263; this version posted June 14, 2017. 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 4.0 International license. 1 2 3 4 43 5 ABSTRACT 6 7 8 44 Background: Decitabine is a deoxycytidine nucleoside derivative inhibitor of DNA- 9 10 45 methyltransferases, which has been studied extensively and is approved for 11 12 13 46 myelodysplastic syndrome in adults but with less focus in children. Accordingly, we 14 15 47 conducted a phase 1 multicenter, randomized, open-label study to evaluate decitabine 16 17 48 pre-treatment before standard induction therapy in children with newly diagnosed AML to 18 19 49 assess safety and tolerability and explore a number of biologic endpoints. 20 21 22 23 50 Results: Twenty-four patients were fully assessable for all study objectives per protocol 24 25 51 (10 in Arm A, 14 in Arm B). All patients experienced neutropenia and thrombocytopenia. 26 27 52 The most common grade 3 and 4 non-hematologic adverse events observed were 28 29 53 gastrointestinal toxicities and hypophosphatemia. Plasma decitabine PK were similar to 30 31 32 54 previously reported adult data. Overall CR/CRi was similar for the two arms. MRD 33 34 55 negativity at end-induction was 85% in Arm A versus 67% in Arm B patients. DNA 35 36 56 methylation measured in peripheral blood over the course of treatment tracked with blast 37 38 57 clearance and matched marrow aspirates at day 0 and day 21. Unlike end-point marrow 39 40 58 analyses, promoter methylation in blood identified an apparent reversal of response in 41 42 43 59 the lone treatment failure, one week prior to the patient’s marrow aspirate confirming 44 45 60 non-response. Decitabine-induced effects of end-induction marrows in Arm A were 46 47 61 reflected by changes in DNA methylation and gene expression comparison with matched 48 49 62 paired marrow diagnostic aspirates. 50 51 52 53 63 Conclusions: This first-in-pediatrics trial demonstrates that decitabine prior to standard 54 55 64 combination chemotherapy is feasible and well tolerated in children with newly 56 57 65 diagnosed AML. Pre-treatment with decitabine may represent a newer therapeutic 58 59 66 option for pediatric AML, especially as it appears to induce important epigenetic 60 61 62 2 63 64 65 bioRxiv preprint doi: https://doi.org/10.1101/124263; this version posted June 14, 2017. 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 4.0 International license. 1 2 3 4 67 alterations. The novel biological correlates studied in this trial offer a clinically relevant 5 6 68 window into disease progression and remission. Additional studies are needed to 7 8 9 69 definitively assess whether decitabine can enhance durability responses in children with 10 11 70 AML. This trial was registered at www.clinicaltrials.gov as NCT01177540. 12 13 14 71 AML, epigenetics, pediatrics, pharmacokinetics, pharmacodynamics, 15 Keywords: 16 17 72 promoter methylation, repeat element transcription 18 19 20 73 21 22 23 24 74 BACKGROUND 25 26 27 28 75 Attaining complete response/remission (CR) is currently considered the essential 29 30 76 first step in the effective treatment of acute myelogenous leukemia (AML). Historically, 31 32 77 the most widely used induction therapy included seven days of cytarabine plus three 33 34 78 days of anthracycline (known as “7+3”). With this approach, 75-80% of children with 35 36 79 37 AML achieve CR (1-3). Subsequently, the addition of a third agent such as etoposide to 38 39 80 7+3 (ADE) along with expanded supportive care measures, has led to higher remission 40 41 81 induction rates of approximately 85%. Of patients who do not attain remission, 42 43 82 approximately one-half have resistant leukemia and a substantial proportion will die from 44 45 83 complications of the disease or treatment. Thus, there is a need to develop new 46 47 48 84 treatment strategies to improve outcomes for these patients. 49 50 85 Pediatric tumors have been shown to have lower mutation burdens than adult 51 52 86 tumors and many of these mutations occur in the plethora of known epigenetic 53 54 87 complexes (4). In addition, significant aberrant DNA methylation is also observed in 55 56 57 88 pediatric cancers such as AML including in patients with the poorest risk sub-types (5). 58 59 89 These studies argue for the importance of identifying novel epigenetic therapies that 60 61 62 3 63 64 65 bioRxiv preprint doi: https://doi.org/10.1101/124263; this version posted June 14, 2017. 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 4.0 International license. 1 2 3 4 90 target both histone and/or DNA methylation modifications. Specifically, reversal of 5 6 91 7 promoter DNA hypermethylation and associated gene silencing is an attractive 8 9 92 therapeutic approach in adult cancers. The DNA methylation inhibitors decitabine and 10 11 93 azacitidine are efficacious for hematological neoplasms at lower, less toxic, doses (6). 12 13 94 Experimentally, high doses induce rapid DNA damage and cytotoxicity, which do not 14 15 95 explain the prolonged response observed in adult patients (6). Studies have consistently 16 17 18 96 shown that transient low doses of DNA demethylating agents exert durable anti-tumor 19 20 97 effects on hematological and epithelial tumor cells (6). Moreover, studies have 21 22 98 demonstrated that DNA hypomethylating agents can sensitize resistant cancer cells to 23 24 99 cytotoxic agents in vitro and in vivo (7-15) and can enhance chemosensitivity of human 25 26 27 100 leukemia cells to cytarabine (16). Therefore, pretreatment with a DNA hypomethylating 28 29 101 agent may increase the efficacy of pediatric AML induction therapy (17). However, to 30 31 102 date there are no studies to demonstrate the safety, tolerability, or any signal of efficacy 32 33 103 of decitabine in combination with conventional multi-agent chemotherapy for AML in 34 35 104 36 children.
Load more

Recommended publications
  • Epigenetics in Clinical Practice: the Examples of Azacitidine and Decitabine in Myelodysplasia and Acute Myeloid Leukemia
    Leukemia (2013) 27, 1803–1812 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu SPOTLIGHT REVIEW Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia EH Estey Randomized trials have clearly demonstrated that the hypomethylating agents azacitidine and decitabine are more effective than ‘best supportive care’(BSC) in reducing transfusion frequency in ‘low-risk’ myelodysplasia (MDS) and in prolonging survival compared with BSC or low-dose ara-C in ‘high-risk’ MDS or acute myeloid leukemia (AML) with 21–30% blasts. They also appear equivalent to conventional induction chemotherapy in AML with 420% blasts and as conditioning regimens before allogeneic transplant (hematopoietic cell transplant, HCT) in MDS. Although azacitidine or decitabine are thus the standard to which newer therapies should be compared, here we discuss whether the improvement they afford in overall survival is sufficient to warrant a designation as a standard in treating individual patients. We also discuss pre- and post-treatment covariates, including assays of methylation to predict response, different schedules of administration, combinations with other active agents and use in settings other than active disease, in particular post HCT. We note that rational development of this class of drugs awaits delineation of how much of their undoubted effect in fact results from hypomethylation and reactivation of gene expression. Leukemia (2013) 27, 1803–1812; doi:10.1038/leu.2013.173
    [Show full text]
  • Clinical Implications of Epigenetics Research
    Clinical Implications of Epigenetics Research Nita Ahuja MD FACS Associate Professor of Surgery, Oncology and Urology Vice Chair of Academic Affairs Chief: Section of GI Oncology & BME Services Epigenetics: Our Software August 1, 2014 2 What is Epigenetics? . Heritable changes in gene expression not due to changes in the DNA sequence . DNA methylation . Chromatin structure or histone code . Role in normal and pathological processes, such as aging, mental health, and cancer, among others. DNA Methylation changes in Neoplasia Normal 1 2 3 Cancer 1 2 3 Epigenetic changes in Neoplasia Normal 1 2 3 AcK9 AcK9 MeK9 MeK9 MeK4 MeK4 MeK27 MeK27 Cancer 1 2 3 MeK9 MeK9 MeK9 MeK9 MeK9 MeK27 MeK27 MeK27 MeK27 MeK27 ?? Epigenetic changes in Neoplasia HATs HDemethylases Normal 1 2 3 AcK9 AcK9 MeK9 MeK9 MeK4 MeK4 MeK27 Aging MeK27 Inflammation HDACs H MTases Cancer 1 2 3 MeK9 MeK9 MeK9 MeK9 MeK9 MeK27 MeK27 MeK27 MeK27 MeK27 ?? Ahuja et. al. Cancer Res. 1998 Issa et. al Cancer Res 2001 Cancer Epigenetics: ApplicationsProtein Repressor proteins RNA (MBD, HDAC) DNA Promoter Gene Cancer Marker for Prognostic Reversal of Gene Silencing Molecular Staging And Predictive Epigenetic Early Detection Biomarkers Therapy Colon Cancer Functional Methylome • Each colon cancer has ~150 to 450 DAC methylated genes/tumor TSA Yellow spots indicate genes from DKO cells with 2 fold changes and above. Green spots indicate experimentally verified genes. Red spots indicate those that did not verify. Blue spots indicate the location of the 11 guide genes used in this study. Schuebel
    [Show full text]
  • Bronchial Biopsy Specimen As a Surrogate for DNA Methylation Analysis in Inoperable Lung Cancer
    Um et al. Clinical Epigenetics (2017) 9:131 DOI 10.1186/s13148-017-0432-5 RESEARCH Open Access Bronchial biopsy specimen as a surrogate for DNA methylation analysis in inoperable lung cancer Sang-Won Um1†, Hong Kwan Kim2†, Yujin Kim3, Bo Bin Lee3, Dongho Kim3, Joungho Han4, Hojoong Kim1, Young Mog Shim2 and Duk-Hwan Kim3,5* Abstract Background: This study was aimed at understanding whether bronchial biopsy specimen can be used as a surrogate for DNA methylation analysis in surgically resected lung cancer. Methods: A genome-wide methylation was analyzed in 42 surgically resected tumor tissues, 136 bronchial washing, 12 sputum, and 8 bronchial biopsy specimens using the Infinium HumanMethylation450 BeadChip, and models for prediction of lung cancer were evaluated using TCGA lung cancer data. Results: Four thousand seven hundred and twenty-six CpGs (P < 1.0E-07) that were highly methylated in tumor tissues were identified from 42 lung cancer patients. Ten CpGs were selected for prediction of lung cancer. Genes including the 10 CpGs were classified into three categories: (i) transcription (HOXA9, SOX17, ZNF154, HOXD13); (ii) cell signaling (HBP1, SFRP1, VIPR2); and (iii) adhesion (PCDH17, ITGA5, CD34). Three logistic regression models based on the 10 CpGs classified 897 TCGA primary lung tissues with a sensitivity of 95.0~97.8% and a specificity of 97.4~98. 7%. However, the classification performance of the models was very poor in bronchial washing samples: the area under the curve (AUC) was equal to 0.72~0.78. The methylation levels of the 10 CpGs in bronchial biopsy were not significantly different from those in surgically resected tumor tissues (P > 0.05, Wilcoxon rank-sum test).
    [Show full text]
  • Phase I Study of Epigenetic Priming With
    Published OnlineFirst November 10, 2016; DOI: 10.1158/1078-0432.CCR-16-1896 Cancer Therapy: Clinical Clinical Cancer Research Phase I Study of Epigenetic Priming with Azacitidine Prior to Standard Neoadjuvant Chemotherapy for Patients with Resectable Gastric and Esophageal Adenocarcinoma: Evidence of Tumor Hypomethylation as an Indicator of Major Histopathologic Response Bryan J. Schneider1, Manish A. Shah1, Kelsey Klute1, Allyson Ocean1, Elizabeta Popa1, Nasser Altorki2, Michael Lieberman3, Andrew Schreiner4, Rhonda Yantiss4, Paul J. Christos5, Romae Palmer6, Daoqi You7, Agnes Viale7, Pouneh Kermani1, and Joseph M. Scandura1,8 Abstract Purpose: Epigenetic silencing of tumor suppressor genes (TSG) by digital droplet, bisulfite qPCR in tumor samples collected at is an acquired abnormality observed in cancer and is prototyp- baseline and at resection. ically linked to DNA methylation. We postulated that pretreat- Results: All subjects underwent complete resection of residual ment (priming) with 5-azacitidine would increase the efficacy of tumor (R0). Three of the 12 patients (25%) achieved a surgical chemotherapy by reactivating TSGs. This study was conducted to complete response and 5 had partial responses. The overall identify a tolerable dose of 5-azacitidine prior to EOX (epirubicin, response rate was 67%. The most common toxicities were gas- oxaliplatin, capecitabine) neoadjuvant chemotherapy in patients trointestinal and hematologic. Hypomethylation of biomarker with locally advanced esophageal/gastric adenocarcinoma genes was observed at all dose levels and trended with therapeutic (EGC). response. Experimental Design: Eligible patients had untreated, locally Conclusions: Neoadjuvant VEOX was well-tolerated with advanced, resectable EGC, ECOG 0–2, and adequate organ func- significant clinical and epigenetic responses, with preliminary tion.
    [Show full text]
  • Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials
    cancers Review Epigenetic Research in Stem Cell Bioengineering—Anti-Cancer Therapy, Regenerative and Reconstructive Medicine in Human Clinical Trials Claudia Dompe 1,2, Krzysztof Janowicz 2,3, Greg Hutchings 2,3, Lisa Moncrieff 1,2, Maurycy Jankowski 3 , Mariusz J. Nawrocki 3 , Małgorzata Józkowiak 4, Paul Mozdziak 5 , Jim Petitte 6 , Jamil A. Shibli 7 , Marta Dyszkiewicz-Konwi ´nska 3,8 , Małgorzata Bruska 3, Hanna Piotrowska-Kempisty 4, Bartosz Kempisty 1,3,9,10,* and Michał Nowicki 1 1 Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; [email protected] (C.D.); l.moncrieff[email protected] (L.M.); [email protected] (M.N.) 2 The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; [email protected] (K.J.); [email protected] (G.H.) 3 Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznan, Poland; [email protected] (M.J.); [email protected] (M.J.N.); [email protected] (M.D.-K.); [email protected] (M.B.) 4 Department of Toxicology, Poznan University of Medical Sciences, 61-631 Poznan, Poland; [email protected] (M.J.); [email protected] (H.P.-K.) 5 Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA; [email protected] 6 Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA; [email protected] 7 Department of Periodontology and Oral Implantology, Dental Research Division, University of Guarulhos, São
    [Show full text]
  • Epigenetic Priming in Drug Addiction
    Epigenetic Priming in Drug Addiction PHILIPP MEWS,DEENA M. WALKER, AND ERIC J. NESTLER Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA Correspondence: [email protected]; [email protected] Drug addiction is a chronic relapsing brain disorder that is characterized by compulsive drug seeking and continued use despite negative outcomes. Current pharmacological therapies target neuronal receptors or transporters upon which drugs of abuse act initially, yet these treatments remain ineffective for most individuals and do not prevent disease relapse after abstinence. Drugs of abuse, in addition to their acute effects, cause persistent plasticity after repeated use, involving dysregulated gene expression in the brain’s reward regions, which are thought to mediate the persistent behavioral abnormalities that characterize addiction. Emerging evidence implicates epigenetic priming as a key mechanism that underlies the long-lasting alterations in neuronal gene regulation, which can remain latent until triggered by re-exposure to drug-associated stimuli or the drug itself. Thus, to effectively treat drug addiction, we must identify the precise epigenetic mechanisms that establish and preserve the drug- induced pathology of the brain reward circuitry. TRANSCRIPTIONAL PRIMING AS A DISEASE long faded (Walker et al. 2015). Permanent (or at least MECHANISM IN DRUG ADDICTION highly stable) changes in neuronal chromatin structure are assumed to underlie such latent dysregulation of tran- Drug addiction is a debilitating neuropsychiatric dis- scription, which is referred to as gene “priming” and order with severe health, financial, and societal conse- “desensitization” (Robison and Nestler 2011; Bastle and quences (Leshner 1997).
    [Show full text]
  • Chidamide, Decitabine, Cytarabine, Aclarubicin, and Granulocyte Colony
    Wang et al. Clinical Epigenetics (2020) 12:132 https://doi.org/10.1186/s13148-020-00923-4 RESEARCH Open Access Chidamide, decitabine, cytarabine, aclarubicin, and granulocyte colony- stimulating factor (CDCAG) in patients with relapsed/refractory acute myeloid leukemia: a single-arm, phase 1/2 study Lixin Wang1,2†, Jianmin Luo3†, Guofeng Chen4,5,6†, Meiyun Fang7, Xudong Wei8, Yinghua Li9, Zhuogang Liu10, Yin Zhang11, Sujun Gao12, Jianliang Shen2, Xin Wang13, Xiaoning Gao6, Wei Zhou5, Yigai Ma14, Hui Liu15, Xinquan Li16, Linhua Yang17, Kai Sun11 and Li Yu1,6* Abstract Background: Epigenetic mechanisms play an important role in the chemoresistance of acute myeloid leukemia (AML). The clinical response to epigenetic modifier-based chemotherapy in patients with relapsed/refractory AML (r/ r AML) is unclear. This multicenter clinical trial evaluated the safety and efficacy of epigenetic modifiers (chidamide and decitabine) in combination with aclarubicin, cytarabine, and granulocyte colony-stimulating factor (G-CSF) in patients with r/r AML. Results: Adult patients with r/r AML were treated with chidamide, decitabine, cytarabine, aclarubicin, and G-CSF (CDCAG). The primary measures were overall response (OR), overall survival (OS), and safety. Next-generation sequencing was performed to analyze the correlation between gene mutations and response. A total of 93 patients with r/r AML were enrolled. Overall, 24 patients had a complete remission (CR) and 19 patients achieved CR with incomplete blood count recovery (CRi). The overall response rate (ORR) was 46.2%. The overall survival of these 43 patients who achieved CR/CRi was significantly longer than that of patients who failed to achieve remission (563 vs 152 days, P < 0.0001).
    [Show full text]
  • Low-Dose DNA Demethylating Therapy Induces Reprogramming of Diverse
    Takeshima et al. Clinical Epigenetics (2020) 12:142 https://doi.org/10.1186/s13148-020-00937-y RESEARCH Open Access Low-dose DNA demethylating therapy induces reprogramming of diverse cancer- related pathways at the single-cell level Hideyuki Takeshima1†, Yukie Yoda1,2†, Mika Wakabayashi1, Naoko Hattori1, Satoshi Yamashita1 and Toshikazu Ushijima1* Abstract Background: Epigenetic reprogramming using DNA demethylating drugs is a promising approach for cancer therapy, but its efficacy is highly dependent on the dosing regimen. Low-dose treatment for a prolonged period shows a remarkable therapeutic efficacy, despite its small demethylating effect. Here, we aimed to explore the mechanisms of how such low-dose treatment shows this remarkable efficacy by focusing on epigenetic reprograming at the single-cell level. Methods: Expression profiles in HCT116 cells treated with decitabine (DAC) were analyzed by single-cell RNA- sequencing (scRNA-seq). Functional consequences and DNA demethylation at the single-cell level were analyzed using cloned HCT116 cells after DAC treatment. Results: scRNA-seq revealed that DAC-treated cells had highly diverse expression profiles at the single-cell level, and tumor-suppressor genes, endogenous retroviruses, and interferon-stimulated genes were upregulated in random fractions of cells. DNA methylation analysis of cloned HCT116 cells revealed that, while only partial reduction of DNA methylation levels was observed in bulk cells, complete demethylation of specific cancer-related genes, such as cell cycle regulation, WNT pathway, p53 pathway, and TGF-β pathway, was observed, depending upon clones. Functionally, a clone with complete demethylation of CDKN2A (p16) had a larger fraction of cells with tetraploid than parental cells, indicating induction of cellular senescence due to normalization of cell cycle regulation.
    [Show full text]
  • The Key Role of DNA Methylation and Histone Acetylation in Epigenetics of Atherosclerosis
    J Lipid Atheroscler. 2020 Sep;9(3):419-434 Journal of https://doi.org/10.12997/jla.2020.9.3.419 Lipid and pISSN 2287-2892·eISSN 2288-2561 Atherosclerosis Review The Key Role of DNA Methylation and Histone Acetylation in Epigenetics of Atherosclerosis Han-Teo Lee ,1,2,* Sanghyeon Oh ,1,2,* Du Hyun Ro ,1,2,3,* Hyerin Yoo ,1,2 Yoo-Wook Kwon 4,5 1Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University, Seoul, Korea 2Interdisciplinary Program in Stem Cell Biology, Graduate School of Medicine, Seoul National University, Seoul, Korea 3Department of Orthopedic Surgery, Seoul National University Hospital, Seoul, Korea 4Strategic Center of Cell and Bio Therapy for Heart, Diabetes & Cancer, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea Received: May 8, 2020 5Department of Medicine, College of Medicine, Seoul National University, Seoul, Korea Revised: Sep 14, 2020 Accepted: Sep 15, 2020 Correspondence to ABSTRACT Yoo-Wook Kwon Biomedical Research Institute, Seoul National Atherosclerosis, which is the most common chronic disease of the coronary artery, constitutes University Hospital, 103 Daehak-ro, Jongno- a vascular pathology induced by inflammation and plaque accumulation within arterial vessel gu, Seoul 03080, Korea. E-mail: [email protected] walls. Both DNA methylation and histone modifications are epigenetic changes relevant for atherosclerosis. Recent studies have shown that the DNA methylation and histone *Han-Teo Lee, Sanghyeon Oh and Du Hyun Ro modification systems are closely interrelated and mechanically dependent on each other. contributed equally to this work. Herein, we explore the functional linkage between these systems, with a particular emphasis Copyright © 2020 The Korean Society of Lipid on several recent findings suggesting that histone acetylation can help in targeting DNA and Atherosclerosis.
    [Show full text]
  • Epigenetic Priming Restores the HLA Class-I Antigen Processing
    www.nature.com/scientificreports OPEN Epigenetic priming restores the HLA class-I antigen processing machinery expression in Merkel cell Received: 24 January 2017 Accepted: 12 April 2017 carcinoma Published: xx xx xxxx Cathrin Ritter1,2,3, Kaiji Fan1,4, Annette Paschen5, Sine Reker Hardrup6, Soldano Ferrone7, Paul Nghiem 8, Selma Ugurel5, David Schrama9 & Jürgen C. Becker 1,2,3,5 Merkel cell carcinoma (MCC) is a rare and aggressive, yet highly immunogenic skin cancer. The latter is due to its viral or UV-associated carcinogenesis. For tumor progression MCC has to escape the host’s immuno-surveillance, e.g. by loss of HLA class-I expression. Indeed, a reduced HLA class-I expression was observed in MCC tumor tissues and MCC cell lines. This reduced HLA class-I surface expression is caused by an impaired expression of key components of the antigen processing machinery (APM), including LMP2 and LMP7 as well as TAP1 and TAP2. Notably, experimental provisions of HLA class-I binding peptides restored HLA class-I surface expression on MCC cells. Silencing of the HLA class-I APM is due to histone deacetylation as inhibition of histone deacetylases (HDACs) not only induced acetylation of histones in the respective promoter regions but also re-expression of APM components. Thus, HDAC inhibition restored HLA class-I surface expression in vitro and in a mouse xenotransplantation model. In contrast to re-induction of HLA class-I by interferons, HDAC inhibitors did not interfere with the expression of immuno-dominant viral proteins. In summary, restoration of HLA class-I expression on MCC cells by epigenetic priming is an attractive approach to enhance therapies boosting adaptive immune responses.
    [Show full text]
  • Epigenetics of Myelodysplastic Syndromes
    Leukemia (2014) 28, 497–506 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu SPOTLIGHT REVIEW Epigenetics of myelodysplastic syndromes R Itzykson1,2,3 and P Fenaux1,2,4 Myelodysplastic syndromes (MDS) are clonal diseases of the elderly characterized by chronic cytopenias, dysplasia and a variable risk of progression to acute myeloid leukemia (AML). Aberrant methylation of tumor-suppressor gene promoters has been established for many years and recently tracked to the most immature cells of MDS, suggesting that these alterations are drivers of MDS pathogenesis. In recent years, recurrent somatic mutations in genes encoding proteins involved in DNA methylation and demethylation and in covalent histone modifications have been reported in myeloid malignancies, including MDS. Whole-genome epigenetic profiles of MDS are also emerging. In parallel with these advances in the molecular pathogenesis of MDS, clinical trials have established hypomethylating agents (HMAs) as the mainstay of therapy in the advanced forms of the disease. In this review, we summarize the current understanding of the molecular machinery involved in epigenetic regulation, discuss how epigenetic alterations arise in MDS and contribute to its pathogenesis and then discuss the mode of action of HMAs in MDS. Leukemia (2014) 28, 497–506; doi:10.1038/leu.2013.343 Keywords: epigenetics; myelodysplastic syndromes; methylation; histone INTRODUCTION number of animal models and human cell lines of MDS, most The notion of ‘epigenetics’ refers to all the information transmitted progresses have come from the study of primary patient samples. through cell division that is not encoded in the DNA sequence. In this Spotlight review, we summarize the current under- However, it is generally used in a restrictive sense as information standing of the molecular machinery involved in epigenetic governing transcription regulation not coded in the DNA regulation, discuss how epigenetic alterations arise in MDS and sequence.
    [Show full text]
  • From Circuits to Chromatin: the Emerging Role of Epigenetics in Mental Health
    The Journal of Neuroscience, 0, 2021 • 00(00):000 • 1 Symposium/Mini-symposium From Circuits to Chromatin: The Emerging Role of Epigenetics in Mental Health Philipp Mews,1 Erin S. Calipari,2 Jeremy Day,3 Mary Kay Lobo,4 Timothy Bredy,5 and Ted Abel6 1Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10129, 2Departments of Pharmacology, Molecular Physiology and Biophysics, Psychiatry and Behavioral Sciences; Vanderbilt Center for Addiction Research; Vanderbilt Brain Institute, Vanderbilt University, Nashville, Tennessee 37323, 3Department of Neurobiology, McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, 4Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, 5Queensland Brain Institute, University of Queensland, Brisbane, 4072, Australia, and 6Department of Neuroscience and Pharmacology, Iowa Neuroscience Institute, University of Iowa, Iowa City, Iowa 52242 A central goal of neuroscience research is to understand how experiences modify brain circuits to guide future adaptive behavior. In response to environmental stimuli, neural circuit activity engages gene regulatory mechanisms within each cell. This activity-dependent gene expression is governed, in part, by epigenetic processes that can produce persistent changes in both neural circuits and the epigenome itself. The complex interplay between circuit activity and neuronal gene regulation is vital to learning and memory, and, when disrupted, is linked to debilitating psychiatric conditions, such as substance use dis- order. To develop clinical treatments, it is paramount to advance our understanding of how neural circuits and the epige- nome cooperate to produce behavioral adaptation. Here, we discuss how new genetic tools, used to manipulate neural circuits and chromatin, have enabled the discovery of epigenetic processes that bring about long-lasting changes in behavior relevant to mental health and disease.
    [Show full text]