DOCSLIB.ORG

Expression of the Tumor Suppressor Krüppel-Like Factor 4 As a Prognostic Predictor for Colon Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Expression of the Tumor Suppressor Krüppel-Like Factor 4 As a Prognostic Predictor for Colon Cancer Published OnlineFirst August 10, 2010; DOI: 10.1158/1055-9965.EPI-10-0677 Cancer Research Article Epidemiology, Biomarkers & Prevention Expression of the Tumor Suppressor Krüppel-Like Factor 4 as a Prognostic Predictor for Colon Cancer Nilesh V. Patel1, Amr M. Ghaleb1, Mandayam O. Nandan1, and Vincent W. Yang1,2 Abstract Background: The zinc finger transcription factor Krüppel-like factor 4 (KLF4) regulates numerous physiologic processes, including proliferation, differentiation, and development. Studies also showed that KLF4 is involved in tumorigenesis and somatic cell reprogramming. Here, we aimed to assess whether KLF4 is a prognostic indicator for colon cancer. Methods: Levels of KLF4 were measured by immunohistochemical analysis of a tissue microarray contain- ing 367 independent colon cancer sections. Univariate data analysis was done in addition to construction of multivariate models with several clinicopathologic factors to evaluate KLF4 as an independent predictor of survival and cancer recurrence (disease-free survival). Results: Colon cancer tissues had significantly overall lower KLF4 levels compared with noncancer tissues (P < 0.0001). Using logistic regression, a trend was noted for decreased odds of KLF4 expression in higher stages of tumors. In univariate and multivariate analyses, KLF4 was a significant predictor of survival and recurrence. Conclusions: KLF4 expression is significantly downregulated in colon cancer, and loss of KLF4 is an independent predictor of survival and recurrence. Impact: These findings suggest that KLF4 may serve as a prognostic biomarker for colon cancer. Cancer Epidemiol Biomarkers Prev; 19(10); 2631–8. ©2010 AACR. Introduction markers independent of established clinicopathologic predictors of the disease. Despite substantial advances in the early diagnosis and Biomarker research in colorectal cancer is becoming treatment of colorectal cancer, it remains a disease with increasingly popular for a variety of clinical and research high morbidity and mortality. Approximately 150,000 applications. Precise biomarkers may be useful as a new cases of colon cancer were diagnosed last year in surrogate endpoint in preliminary studies, for the strati- the United States, making it the fourth most common fication of patients in clinical trials, and in the refinement cancer diagnosed in men and women (1). It is also the of disease prognosis. The debate surrounding the role of second most common cause of cancer-related death chemotherapeutics in American Joint Committee on despite a recent reduction in mortality due to increased Cancer (AJCC) stage II colon cancer provides an example screening and improvements in treatment for late-stage of such an application. Within the past decade, a number cancer (2). Studies have identified mutations in tumor of new systemic treatments for colon cancer, including suppressor genes and oncogenes that result in dysregula- oral fluropyrimidines, oxaliplatin, and irinotecan, have tion of numerous pathways leading to colorectal carcino- been shown to improve overall and disease-free survival genesis (3, 4). Nonetheless, future research in colorectal in stage III cancer patients (5). Unlike patients with third- cancer depends on the ability to conduct research relative stage cancer, current recommendations by the American to potential applications of available data, translate the Society of Clinical Oncology do not promote the routine mechanistic data into the clinical arena, and evaluate use of chemotherapeutics in stage II cancer (6). Although no clinical trial has proven overall benefit of adjuvant therapy in stage II, it is hypothesized that up to 20% of patients with a risk for recurrence similar to that of stage Authors' Affiliations: 1Division of Digestive Diseases, Departments of III disease would have benefited from chemotherapeutics Medicine and 2Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia (5). Currently, the American Society of Clinical Oncology suggests that patients with inadequately sampled nodes, Corresponding Author: Vincent W. Yang, Division of Digestive Diseases, Department of Medicine, Emory University School of Medicine, 615 T4 lesions, perforation, or poorly differentiated histology Michael Street, Atlanta, GA 30322. Phone: 404-727-5638; Fax: 404- should at least be considered for such treatment at the 727-5767. E-mail: [email protected] discretion of the treating physician and patient (6). How- doi: 10.1158/1055-9965.EPI-10-0677 ever, no studies have evaluated the benefit of such a rec- ©2010 American Association for Cancer Research. ommendation or whether the suggested criteria correctly www.aacrjournals.org 2631 Downloaded from cebp.aacrjournals.org on September 25, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst August 10, 2010; DOI: 10.1158/1055-9965.EPI-10-0677 Patel et al. predict recurrence risk. Biomarkers may prove especially in duplicate because 2-fold redundancy permits accurate useful in further stratifying stage II patients into those analysis of protein expression (34). who have a high risk for recurrence and those who do The paraffin-fixed colon tissue microarray was con- not, the former group being more likely to benefit from structed between 1989 and 1996 by the National Cancer chemotherapeutics. Several biomarkers such as S-phase Institute's Cancer Diagnosis Program of the National fractions and vascular endothelial growth factor expres- Cancer Institute (35). The microarray was assembled sion have been evaluated in this regard (7, 8). using 367 cores of colon cancer (49 stage I, 122 stage II, Krüppel-like factors (KLF) are a family of evolutionarily 144 stage III, and 52 stage IV), 37 cores of adenomatous conserved mammalian zinc finger transcription factors polyps, 34 cores of normal colon tissues matched to tu- named for their homology with Krüppel, a Drosophila mor sections, and an additional 40 normal colon sections melanogaster protein (9). KLFs are involved in a diverse from individuals with diverticulosis. Of the colon cancer array of fundamental biological processes, including cases, 5-year follow up data were complete on 96 stage proliferation, differentiation, development, and apoptosis II tumors (26 recurred) and 125 stage III tumors (10-12). Among the KLF family, KLF4 (also called gut- (65 recurred). Of all stage II and III tumors, 45 were cen- enriched KLF or GKLF) was one of the first identified sored before the 5-year follow up was complete. Nonco- (13, 14). In addition to regulating many important phys- lon tissue cores were embedded on the microarrays for iologic processes, KLF4 has been shown to play a role in internal control of staining. In addition, cores from colon pathologic conditions such as cancer and inflammation cancer cell lines were embedded as additional internal (15-20). More recently, KLF4 was shown to play a crucial controls. These cell lines were characterized and authen- role in the reprogramming of somatic cells into induced ticated by the National Cancer Institute under American pluripotent stem cells (21-25). Type Culture Collection guidelines (35). Of all patients, Expression of KLF4 is enriched in epithelial tissues, 418 were Caucasian, 12 were African American, and 11 including the gut (13, 14). In the intestine, KLF4 is highly identified with another race. Two hundred and seven expressed in the postmitotic, terminally differentiated subjects were male, and 233 were female (gender of one in- epithelial cells at the luminal surface (26, 27). In vitro, dividual was unknown). Mean age was 68.62 (SD, 12.48). KLF4 inhibits proliferation by blocking cell cycle prog- Additional covariate data were collected on tumor depth, ression at the G1/S boundary (28). In addition, KLF4 nodal status, metastasis, histology, location, and degree of mediates the cell cycle checkpoint functions of the tumor dysplasia as assessed by an independent pathologist. suppressor p53 following DNA damage (29-31). More- Selection of patients across various stages was done to over, loss of expression of KLF4 due to several reasons, ensure enough power to detect differences in recurrence including loss of heterozygosity, promoter hypermethy- within stage II and stage III cancer independently. The lation, and loss-of-function mutations, has been docu- cases were chosen to detect a difference in the prevalence mented in a small set of colorectal cancer specimens rate of 0.35 within stage II or III tumors that recurred and (32). This tumor suppressive effect of KLF4 is supported those that did not within the 5-year follow-up period. To by in vivo evidence in which mice heterozygous for detect differences in a binary outcome marker across var- Klf4 manifest increased tumor burden when bred to the ious stages of disease, enough stage I and IV tumors were ApcMin mice that are genetically predisposed to intestinal also included, so >80% power was available to detect a adenoma formation (17). From a mechanistic perspective, 0.30 difference in prevalence rate of KLF4 (see Guidance KLF4 inhibits Wnt signaling, a key pathway in colorectal for Statistical Analysis of Biomarker Data Generated carcinogenesis, by inhibiting the activity of β-catenin, a from the NCI Colon Tissue Microarray; ref. 36). mediator of Wnt signaling (33). Because of its putative tumor suppressor function, Immunohistochemistry KLF4 may serve as a prognostic indicator for colon can- The microarrays were treated with xylene for deparaf- cer. Here, we measured KLF4 expression levels in
Load more

Recommended publications
  • Microglia Emerge from Erythromyeloid Precursors Via Pu.1- and Irf8-Dependent Pathways
    ART ic LE S Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways Katrin Kierdorf1,2, Daniel Erny1, Tobias Goldmann1, Victor Sander1, Christian Schulz3,4, Elisa Gomez Perdiguero3,4, Peter Wieghofer1,2, Annette Heinrich5, Pia Riemke6, Christoph Hölscher7,8, Dominik N Müller9, Bruno Luckow10, Thomas Brocker11, Katharina Debowski12, Günter Fritz1, Ghislain Opdenakker13, Andreas Diefenbach14, Knut Biber5,15, Mathias Heikenwalder16, Frederic Geissmann3,4, Frank Rosenbauer6 & Marco Prinz1,17 Microglia are crucial for immune responses in the brain. Although their origin from the yolk sac has been recognized for some time, their precise precursors and the transcription program that is used are not known. We found that mouse microglia were derived from primitive c-kit+ erythromyeloid precursors that were detected in the yolk sac as early as 8 d post conception. + lo − + − + These precursors developed into CD45 c-kit CX3CR1 immature (A1) cells and matured into CD45 c-kit CX3CR1 (A2) cells, as evidenced by the downregulation of CD31 and concomitant upregulation of F4/80 and macrophage colony stimulating factor receptor (MCSF-R). Proliferating A2 cells became microglia and invaded the developing brain using specific matrix metalloproteinases. Notably, microgliogenesis was not only dependent on the transcription factor Pu.1 (also known as Sfpi), but also required Irf8, which was vital for the development of the A2 population, whereas Myb, Id2, Batf3 and Klf4 were not required. Our data provide cellular and molecular insights into the origin and development of microglia. Microglia are the tissue macrophages of the brain and scavenge dying have the ability to give rise to microglia and macrophages in vitro cells, pathogens and molecules using pattern recognition receptors and in vivo under defined conditions.
    [Show full text]
  • A Dual Cis-Regulatory Code Links IRF8 to Constitutive and Inducible Gene Expression in Macrophages
    Downloaded from genesdev.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press A dual cis-regulatory code links IRF8 to constitutive and inducible gene expression in macrophages Alessandra Mancino,1,3 Alberto Termanini,1,3 Iros Barozzi,1 Serena Ghisletti,1 Renato Ostuni,1 Elena Prosperini,1 Keiko Ozato,2 and Gioacchino Natoli1 1Department of Experimental Oncology, European Institute of Oncology (IEO), 20139 Milan, Italy; 2Laboratory of Molecular Growth Regulation, Genomics of Differentiation Program, National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland 20892, USA The transcription factor (TF) interferon regulatory factor 8 (IRF8) controls both developmental and inflammatory stimulus-inducible genes in macrophages, but the mechanisms underlying these two different functions are largely unknown. One possibility is that these different roles are linked to the ability of IRF8 to bind alternative DNA sequences. We found that IRF8 is recruited to distinct sets of DNA consensus sequences before and after lipopolysaccharide (LPS) stimulation. In resting cells, IRF8 was mainly bound to composite sites together with the master regulator of myeloid development PU.1. Basal IRF8–PU.1 binding maintained the expression of a broad panel of genes essential for macrophage functions (such as microbial recognition and response to purines) and contributed to basal expression of many LPS-inducible genes. After LPS stimulation, increased expression of IRF8, other IRFs, and AP-1 family TFs enabled IRF8 binding to thousands of additional regions containing low-affinity multimerized IRF sites and composite IRF–AP-1 sites, which were not premarked by PU.1 and did not contribute to the basal IRF8 cistrome.
    [Show full text]
  • Genequery™ Human Stem Cell Transcription Factors Qpcr Array
    GeneQuery™ Human Stem Cell Transcription Factors qPCR Array Kit (GQH-SCT) Catalog #GK125 Product Description ScienCell's GeneQuery™ Human Stem Cell Transcription Factors qPCR Array Kit (GQH-SCT) surveys a panel of 88 transcription factors related to stem cell maintenance and differentiation. Transcription factors are proteins that can regulate target gene transcription level by binding to specific regions of the genome known as enhancers or silencers. Brief examples of how genes may be grouped according to their functions are shown below: • Pluripotency transcription factors: NANOG, POU5F1, SOX2 • Embryonic development: EOMES, FOXC2/D3/O1, HOXA9/A10, KLF2/5, LIN28B, MAX, PITX2, SMAD1, TBX5, ZIC1 • Germ layer formation and differentiation: FOXA2, GATA6, HAND1, ISL1, KLF4, SMAD2, SOX9 • Organ morphogenesis: EZH2, HOXA11/B3/B5/C9, MSX2, MYC, PAX5/8, VDR • Angiogenesis: CDX2, JUN, NR2F2, RUNX1, WT1 • Hematopoiesis and osteogenesis: EGR3, ESR1, GATA1/2/3, GLI2, NFATC1, PAX9, RB1, SOX6, SP1, STAT1 • Neural stem cell maintenance and differentiation: ATF2, CREB1, FOSB, FOXO3, HES1, HOXD10, MCM2/7, MEF2C, NEUROD1/G1, OLIG1/2, PAX3/6, POU4F1, PPARG, SMAD3/4, SNAI1, STAT3 Note : all gene names follow their official symbols by the Human Genome Organization Gene Nomenclature Committee (HGNC). GeneQuery™ qPCR array kits are qPCR ready in a 96-well plate format, with each well containing one primer set that can specifically recognize and efficiently amplify a target gene's cDNA. The carefully designed primers ensure that: (i) the optimal annealing temperature in qPCR analysis is 65°C (with 2 mM Mg 2+ , and no DMSO); (ii) the primer set recognizes all known transcript variants of target gene, unless otherwise indicated; and (iii) only one gene is amplified.
    [Show full text]
  • Krüppel-Like Factor 4 Promotes Survival and Expansion in Acute Myeloid Leukemia Cells
    www.oncotarget.com Oncotarget, 2021, Vol. 12, (No. 4), pp: 255-267 Research Paper Krüppel-like factor 4 promotes survival and expansion in acute myeloid leukemia cells Andrew Henry Lewis1, Cory Seth Bridges1, Viraaj Singh Punia1, Abraham Fausto Jornada Cooper1,2, Monica Puppi1 and H. Daniel Lacorazza1 1Department of Pathology & Immunology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX 77030, USA 2SMART Program at Baylor College of Medicine Houston, Houston, TX 77030, USA Correspondence to: H. Daniel Lacorazza, email: [email protected] Keywords: acute myeloid leukemia; KLF4; cancer; gene editing; cell growth Received: November 20, 2020 Accepted: January 19, 2021 Published: February 16, 2021 Copyright: © 2021 Lewis et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Acute myeloid leukemia (AML) is an aggressive hematological malignancy of the bone marrow that affects mostly elderly adults. Alternative therapies are needed for AML patients because the overall prognosis with current standard of care, high dose chemotherapy and allogeneic transplantation, remains poor due to the emergence of refractory and relapsed disease. Here, we found expression of the transcription factor KLF4 in AML cell lines is not silenced through KLF4 gene methylation nor via proteasomal degradation. The deletion of KLF4 by CRISPR-CAS9 technology reduced cell growth and increased apoptosis in both NB4 and MonoMac-6 cell lines. Chemical induced differentiation of gene edited NB4 and MonoMac6 cells with ATRA and PMA respectively increased apoptosis and altered expression of differentiating markers CD11b and CD14.
    [Show full text]
  • ERG Promotes Transcriptional Reprogramming of Prostatic Epithelial Cells Toward a Cancer Stem Cell Phenotype
    ERG promotes transcriptional reprogramming of prostatic epithelial cells toward a cancer stem cell phenotype Manju Sharma, Yubin Guo, Robert Bell, and Michael E. Cox. Vancouver Prostate Centre. Vancouver British Columbia, Canada Abstract Genomic rearrangements that result in aberrant expression of the proto-oncogene member of the erythroblast transformation-specific family of transcription factors, ERG, occur in almost half of prostate cancers. The most frequent rearrangements are the result of an interstitial deletion that results in fusion of androgen-responsive elements of serine 2-erythroblast transformation-specific-related gene with variable amino terminal ERG open reading frame exons. These TMPRSS2-ERG fusions are the most common cancer-associated mutation. They occur early in prostate cancer initiation, are associated with high Gleason score, and aggressive disease. When amplified and/or expressed at high level, TMPRSS2-ERG is associated with poor prognosis. Mirroring its functions in normal chondrocyte and endothelial cell differentiation, ERG expression in prostatic epithelial cells drives aberrant activation of transcriptional programs promoting migration, invasion, and epithelial-mesenchymal transition. Additionally, TMPRSS2-ERG status appears to enhance resistance to abiraterone and taxane therapies. We hypothesized that ERG expression can promote transformation of prostatic epithelial cells by directing transcriptional reprogramming towards a cancer stem cell phenotype. Transcriptional analysis of ERG-expressing RWPE1 prostatic epithelial cells (ERG-RWPE1) demonstrated up-regulation transcription of a panel of stem cell-related genes. When cultured under non- adherent conditions, ERG-RWPE1 cells selectively demonstrated the ability of form serially passable spheroids and dramatically increased expression of stem cell markers, PROM1, c-KIT and CD33. When re- plated in adherent conditions, cells re-established the expression pattern of parental adherent cultures.
    [Show full text]
  • KLF4 Suppresses Estrogen-Dependent Breast Cancer Growth by Inhibiting the Transcriptional Activity of Era
    Oncogene (2009) 28, 2894–2902 & 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00 www.nature.com/onc ORIGINAL ARTICLE KLF4 suppresses estrogen-dependent breast cancer growth by inhibiting the transcriptional activity of ERa K Akaogi1, Y Nakajima1, I Ito1, S Kawasaki1, S-h Oie1, A Murayama1,2,3, K Kimura1 and J Yanagisawa1,2 1Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan; 2TARA Center, University of Tsukuba, Tsukuba Science City, Ibaraki, Japan and 3PRESTO, JST, 4-1-8 Honcho Kawaguchi, Saitama, Japan Kruppel-like factor 4 (KLF4) is a transcription factor that et al., 1999, 2000; Nickenig et al., 2002; Chen et al., participates in both tumor suppression and oncogenesis. 2003). This indicates that KLF4 regulates the expression To determine the association of KLF4 with tumorigenesis, of a set of cell-cycle genes to coordinately inhibit cellular we integrated data assembled in the Oncomine database proliferation. in vivo, KLF4 is essential for maintaining and discovered a decrease in KLF4 gene transcripts in terminally differentiated epithelial cells in the lung, skin breast cancers. Further analysis of the database also and gastrointestinal tract (Shields et al., 1996; Segre showed a correlation between KLF4 expression and et al., 1999; Jaubert et al., 2003; Blanchon et al., 2006; estrogen receptor-a (ERa) positivity. Knockdown of Patel et al., 2006). In cultured cells, KLF4 expression is KLF4 in MCF-7 cells elevated the growth rate of these temporally associated with conditions that promote cells in the presence of estrogen. Therefore, we examined growth arrest, such as serum deprivation, contact the interaction between KLF4 and ERa, and found that inhibition and DNA damage, and constitutive KLF4 KLF4 bound to the DNA-binding region of ERa.
    [Show full text]
  • Engineered Stem Cells in Hematologic Diseases
    Next Generation Transplantation: Engineered Stem Cells in Hematologic Diseases George Q. Daley Boston Children’s Hospital/ Harvard Medical School/ HHMI Tandem Meetings 2016 Disclosures: Scientific Advisory Boards (consulting fees and equity) MPM Capital, Solasia, Epizyme, Ocata, Raze, True North, Verastem, AthenaHealth Research Funding: Megakaryon Boston Children’s/ Dana Farber Pediatric Stem Cell Transplant 2015: 114 Transplants Leslie Lehmann Christy Duncan Nick Haining Clinical Director Assoc. Clinical Dir. Assoc. Scientific Dir. Alessandra Biffi Director Gene Therapy Steve Margossian Sung-Yun Pai Suneet Agarwal Michelle Lee Christy Ullirch Jen Whangbo Susanne Baumeister Esther Obang Leo Wang Birgit Knoechel Inga Hoffman Autologous Cell Therapy from iPS Cells NSG Transplant Skin or Blood Cell Primary Immune Deficiency Hematopoietic Bone Marrow Failure stem cells Hemoglobinopathy Reprogramming (Oct4/Sox2/Klf4/Myc) ? Gene Repair Diseased iPS cells Healthy iPS cells ES/ iPS Mammalian Embryoidblood development:Bodies Primitive and Definitive= Yolk Sac waves Morphogens? Drugs? Transcription Factors? Strategies for deriving HSCs from HUMAN pluripotent stem cells (ESC/iPSCs) HSC-specific TFs ?? Respecification CD34+43- ESC/iPSC Hemogenic HSC? CD34+ Endothelium CD45+ TFs Myeloid CFUs Specification Morphogens Respecifying blood progenitors from iPSCs hESC/iPSC EB differentiation - BMP4/cytokines CD34+45+ HPCs D0 D4-7 D11+ D14 HSC TFs 7+ days 9 HSC TFs: Transplant HLF ERG Control MYB SOX4 CD34+45+ KLF4 HPCs RORA Microarray HOXA5 HOXA9 HOXA10
    [Show full text]
  • The AP-1 Transcription Factor C-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages
    The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages This information is current as of September 28, 2021. Nicole Hannemann, Jutta Jordan, Sushmita Paul, Stephen Reid, Hanns-Wolf Baenkler, Sophia Sonnewald, Tobias Bäuerle, Julio Vera, Georg Schett and Aline Bozec J Immunol published online 15 March 2017 http://www.jimmunol.org/content/early/2017/03/15/jimmun Downloaded from ol.1601330 Supplementary http://www.jimmunol.org/content/suppl/2017/03/15/jimmunol.160133 http://www.jimmunol.org/ Material 0.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2017 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published March 15, 2017, doi:10.4049/jimmunol.1601330 The Journal of Immunology The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages Nicole Hannemann,* Jutta Jordan,† Sushmita Paul,‡ Stephen Reid,x Hanns-Wolf Baenkler,* Sophia Sonnewald,x Tobias Ba¨uerle,† Julio Vera,‡ Georg Schett,* and Aline Bozec* Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis.
    [Show full text]
  • Roles of Krüppel Like Factors Klf1, Klf2, and Klf4 in Embryonic Beta-Globin Gene Expression
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2009 ROLES OF KRÜPPEL LIKE FACTORS KLF1, KLF2, AND KLF4 IN EMBRYONIC BETA-GLOBIN GENE EXPRESSION Yousef Alhashem Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Medical Genetics Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/1880 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. Virginia Commonwealth University School of Medicine This is to certify that the thesis prepared by Yousef N. Alhashem entitled “Roles Of Krüppel Like Factors KLF1, KLF2, And KLF4 In Embryonic Beta-Globin Gene Expression” has been approved by the student advisory committee as a satisfactory for the completion of the thesis reqirement for the degree of Master of Science. _____________________________________________ Joyce A. Lloyd, Ph.D., Director of Thesis, School of Medicine _____________________________________________ Rita Shiang, Ph.D., School of Medicine _____________________________________________ David C. Williams Jr., Ph.D., School of Medicine _____________________________________________ Paul B. Fisher, Ph.D., Chair, Department of Human and Molecular Genetics _____________________________________________ Jerome F. Strauss, III, M.D., Ph.D., Dean, School of Medicine _____________________________________________ F. Douglas Boudinot, Ph.D., Dean, Graduate School _____________________________________________ Date © Yousef Nassir Alhashem 2009 ROLES OF KRÜPPEL LIKE FACTORS KLF1, KLF2, AND KLF4 IN EMBRYONIC BETA-GLOBIN GENE EXPRESSION A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University By Yousef Nassir Alhashem, B.Sc.
    [Show full text]
  • Molecular Classification of Prostate Cancer Using Curated Expression
    Molecular classification of prostate cancer using curated expression signatures Elke K. Markerta, Hideaki Mizunob,c, Alexei Vazqueza,d,e, and Arnold J. Levinea,d,f,1 aSimons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ 08540; bDiscovery Science and Technology Department, Chugai Pharmaceutical, Kamakura, Kanagawa 247-8530, Japan; cDepartment of Bioscience and Bioinformatics, Kyushu Institute of Technology, Iizuka, Fukuoka 820-8502, Japan; dThe Cancer Institute of New Jersey, New Brunswick, NJ 08901; eDepartment of Radiation Oncology, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ 08903; and fDepartment of Pediatrics and Biochemistry, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ 08903 Contributed by Arnold J. Levine, October 21, 2011 (sent for review September 6, 2011) High Gleason score is currently the best prognostic indicator for be related to the efficient production of iPS cells from fibroblasts poor prognosis in prostate cancer. However, a significant number after the introduction of four transcription factors, Myc, Klf4, of patients with low Gleason scores develop aggressive disease as Oct4, and Sox2 (6). In the absence of p53 activity, Oct4 and Sox2 well. In an effort to understand molecular signatures associated can increase the efficiency of producing iPS cells from 0.1% up with poor outcome in prostate cancer, we analyzed a microarray to 80% and accomplish this in 5–6 d instead of 2 wk (7–11). dataset characterizing 281 prostate cancers from a Swedish watch- Thus, p53 appears to block or reduce the production of an ESC ful-waiting cohort.
    [Show full text]
  • Inactivation of the P53–KLF4–CEBPA Axis in Acute Myeloid Leukemia Katja Seipel1,2, Miguel Teixera Marques1, Marie-Ange Bozzini1, Christina Meinken1, Beatrice U
    Published OnlineFirst September 25, 2015; DOI: 10.1158/1078-0432.CCR-15-1054 Biology of Human Tumors Clinical Cancer Research Inactivation of the p53–KLF4–CEBPA Axis in Acute Myeloid Leukemia Katja Seipel1,2, Miguel Teixera Marques1, Marie-Ange Bozzini1, Christina Meinken1, Beatrice U. Mueller1, and Thomas Pabst2 Abstract Purpose: In acute myeloid leukemia (AML), the transcription of p53 function and concomitant reduction of KLF4 and CEBPA factors CEBPA and KLF4 as well as the universal tumor suppressor protein levels. Assessment of cellular p53 modulator proteins p53 are frequently deregulated. Here, we investigated the extent of indicated that p53 inactivation in leukemic cells correlated with dysregulation, the molecular interactions, and the mechanisms elevated levels of the nuclear export protein XPO1/CRM1 and involved. increase of the p53 inhibitors MDM2 and CUL9/PARC in the Experimental Design: One hundred ten AML patient samples cytoplasm. Finally, restoring p53 function following treatment were analyzed for protein levels of CEBPA, KLF4, p53, and p53 with cytotoxic chemotherapy compounds and p53 restoring non- modulators. Regulation of CEBPA gene expression by KLF4 and genotoxic agents induced CEBPA gene expression, myeloid dif- p53 or by chemical p53 activators was characterized in AML cell ferentiation, and cell-cycle arrest in AML cells. lines. Conclusions: The p53–KLF4–CEBPA axis is deregulated in Results: We found that CEBPA gene transcription can be AML but can be functionally restored by conventional chemo- directly activated by p53 and KLF4, suggesting a p53–KLF4– therapy and novel p53 activating treatments. Clin Cancer Res; 22(3); CEBPA axis. In AML patient cells, we observed a prominent loss 746–56.
    [Show full text]
  • HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development
    Published OnlineFirst March 1, 2018; DOI: 10.1158/2159-8290.CD-17-0583 RESEARCH ARTICLE HOXA9 Cooperates with Activated JAK/STAT Signaling to Drive Leukemia Development Charles E. de Bock 1 , 2 , Sofi e Demeyer 1 , 2 , Sandrine Degryse 1 , 2 , Delphine Verbeke 1 , 2 , Bram Sweron 1 , 2 , Olga Gielen 1 , 2 , Roel Vandepoel 1 , 2 , Carmen Vicente 1 , 2 , Marlies Vanden Bempt 1 , 2 , Antonis Dagklis 1 , 2 , Ellen Geerdens 1 , 2 , Simon Bornschein 1 , 2 , Rik Gijsbers 3 , Jean Soulier 4 , Jules P. Meijerink 5 , Merja Heinäniemi 6 , Susanna Teppo 7 , Maria Bouvy-Liivrand 6 , Olli Lohi 7 , Enrico Radaelli 1 , 2 , and Jan Cools 1 , 2 ABSTRACT Leukemia is caused by the accumulation of multiple genomic lesions in hemato- poietic precursor cells. However, how these events cooperate during oncogenic transformation remains poorly understood. We studied the cooperation between activated JAK3/ STAT5 signaling and HOXA9 overexpression, two events identifi ed as signifi cantly co-occurring in T-cell acute lymphoblastic leukemia. Expression of mutant JAK3 and HOXA9 led to a rapid development of leukemia originating from multipotent or lymphoid-committed progenitors, with a signifi cant decrease in disease latency compared with JAK3 or HOXA9 alone. Integrated RNA sequencing, chromatin immu- noprecipitation sequencing, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC- seq) revealed that STAT5 and HOXA9 have co-occupancy across the genome, resulting in enhanced STAT5 transcriptional activity and ectopic activation of FOS/JUN (AP1). Our data suggest that onco- genic transcription factors such as HOXA9 provide a fertile ground for specifi c signaling pathways to thrive, explaining why JAK/STAT pathway mutations accumulate in HOXA9-expressing cells.
    [Show full text]