CBF---A Biophysical Perspective
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Transcriptome Profiling of Pediatric Core Binding Factor AML
RESEARCH ARTICLE Transcriptome Profiling of Pediatric Core Binding Factor AML Chih-Hao Hsu1, Cu Nguyen1, Chunhua Yan1, Rhonda E. Ries2, Qing-Rong Chen1, Ying Hu1, Fabiana Ostronoff2, Derek L. Stirewalt2, George Komatsoulis1, Shawn Levy3, Daoud Meerzaman1☯, Soheil Meshinchi2☯* 1 Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, MD, 20850, United States of America, 2 Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America, 3 Hudson Alpha Institute for Biotechnology, Huntsville, AL, United States of America ☯ These authors contributed equally to this work. * [email protected] Abstract The t(8;21) and Inv(16) translocations disrupt the normal function of core binding factors alpha (CBFA) and beta (CBFB), respectively. These translocations represent two of the most com- OPEN ACCESS mon genomic abnormalities in acute myeloid leukemia (AML) patients, occurring in approxi- Citation: Hsu C-H, Nguyen C, Yan C, Ries RE, Chen mately 25% pediatric and 15% of adult with this malignancy. Both translocations are Q-R, Hu Y, et al. (2015) Transcriptome Profiling of associated with favorable clinical outcomes after intensive chemotherapy, and given the per- Pediatric Core Binding Factor AML. PLoS ONE 10(9): ceived mechanistic similarities, patients with these translocations are frequently referred to as e0138782. doi:10.1371/journal.pone.0138782 having CBF-AML. It remains uncertain as to whether, collectively, these translocations are Editor: Ken Mills, Queen's University Belfast, mechanistically the same or impact different pathways in subtle ways that have both biological UNITED KINGDOM and clinical significance. Therefore, we used transcriptome sequencing (RNA-seq) to investi- Received: June 15, 2015 gate the similarities and differences in genes and pathways between these subtypes of pediat- Accepted: September 3, 2015 ric AMLs. -
Core Binding Factor Β Is Required for Group 2 Innate Lymphoid Cell Activation
Cutting Edge: Core Binding Factor β Is Required for Group 2 Innate Lymphoid Cell Activation This information is current as Xiaofei Shen, Mingwei Liang, Xiangyu Chen, Muhammad of September 24, 2021. Asghar Pasha, Shanti S. D'Souza, Kelsi Hidde, Jennifer Howard, Dil Afroz Sultana, Ivan Ting Hin Fung, Longyun Ye, Jiexue Pan, Gang Liu, James R. Drake, Lisa A. Drake, Jinfang Zhu, Avinash Bhandoola and Qi Yang J Immunol 2019; 202:1669-1673; Prepublished online 6 Downloaded from February 2019; doi: 10.4049/jimmunol.1800852 http://www.jimmunol.org/content/202/6/1669 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2019/02/05/jimmunol.180085 Material 2.DCSupplemental References This article cites 20 articles, 10 of which you can access for free at: http://www.jimmunol.org/content/202/6/1669.full#ref-list-1 Why The JI? Submit online. by guest on September 24, 2021 • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • 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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. -
Supplemental Information For
Supplemental Information for: Gene Expression Profiling of Pediatric Acute Myelogenous Leukemia Mary E. Ross, Rami Mahfouz, Mihaela Onciu, Hsi-Che Liu, Xiaodong Zhou, Guangchun Song, Sheila A. Shurtleff, Stanley Pounds, Cheng Cheng, Jing Ma, Raul C. Ribeiro, Jeffrey E. Rubnitz, Kevin Girtman, W. Kent Williams, Susana C. Raimondi, Der-Cherng Liang, Lee-Yung Shih, Ching-Hon Pui & James R. Downing Table of Contents Section I. Patient Datasets Table S1. Diagnostic AML characteristics Table S2. Cytogenetics Summary Table S3. Adult diagnostic AML characteristics Table S4. Additional T-ALL characteristics Section II. Methods Table S5. Summary of filtered probe sets Table S6. MLL-PTD primers Additional Statistical Methods Section III. Genetic Subtype Discriminating Genes Figure S1. Unsupervised Heirarchical clustering Figure S2. Heirarchical clustering with class discriminating genes Table S7. Top 100 probe sets selected by SAM for t(8;21)[AML1-ETO] Table S8. Top 100 probe sets selected by SAM for t(15;17) [PML-RARα] Table S9. Top 63 probe sets selected by SAM for inv(16) [CBFβ-MYH11] Table S10. Top 100 probe sets selected by SAM for MLL chimeric fusion genes Table S11. Top 100 probe sets selected by SAM for FAB-M7 Table S12. Top 100 probe sets selected by SAM for CBF leukemias (whole dataset) Section IV. MLL in combined ALL and AML dataset Table S13. Top 100 probe sets selected by SAM for MLL chimeric fusions irrespective of blast lineage (whole dataset) Table S14. Class discriminating genes for cases with an MLL chimeric fusion gene that show uniform high expression, irrespective of blast lineage Section V. -
Steffensen Et Al. Supplement 2A
Liver Wild-type Knockout 1 2 4 1 2 4 1 1 1 C C C C C C W W W K K K IMAGE:640919 expressed sequence AA960558 IMAGE:523974 RIKEN cDNA 1810004N01 gene IMAGE:1211217 eukaryotic translation initiation factor 4E binding protein 2 IMAGE:314741 beta-site APP cleaving enzyme IMAGE:1038420 silica-induced gene 41 IMAGE:1229655 soc-2 suppressor of clear homolog C. elegans IMAGE:1150065 Unknown IMAGE:1038486 RIKEN cDNA 2700038M07 gene IMAGE:524351 amyloid beta A4 precursor protein IMAGE:819912 thymus expressed acidic protein IMAGE:779426 RIKEN cDNA 5230400G24 gene IMAGE:945643 ESTs IMAGE:850544 Mpv17 transgene, kidney disease mutant IMAGE:537568 expressed sequence AA675315 IMAGE:1107584 yes-associated protein, 65 kDa IMAGE:961363 expressed sequence AU015422 IMAGE:775218 expressed sequence AI265322 IMAGE:792656 protein phosphatase 1B, magnesium dependent, beta isoform IMAGE:1038592 ESTs, Weakly similar to A43932 mucin 2 precursor, intestinal [H.sapiens] IMAGE:1224917 huntingtin interacting protein 2 IMAGE:751186 ESTs IMAGE:865151 Trk-fused gene IMAGE:523016 SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 5 IMAGE:765039 FBJ osteosarcoma oncogene B IMAGE:1003995 expressed sequence AI844632 IMAGE:903863 RIKEN cDNA 1300006L01 gene IMAGE:934094 ESTs IMAGE:988962 expressed sequence C77245 IMAGE:1023308 ESTs, Weakly similar to S71512 hypothetical protein T2 - mouse [M.musculus] IMAGE:865317 eukaryotic translation initiation factor 3 IMAGE:720445 ribosomal protein S6 IMAGE:1005417 expressed sequence AU024550 -
Smac Mimetic Induces Cell Death in a Large Proportion of Primary Acute Myeloid Leukemia Samples, Which Correlates with Defined Molecular Markers
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 31 Research Paper Smac mimetic induces cell death in a large proportion of primary acute myeloid leukemia samples, which correlates with defined molecular markers Sonja C. Lueck1, Annika C. Russ1, Ursula Botzenhardt1, Richard F. Schlenk1, Kerry Zobel2, Kurt Deshayes2, Domagoj Vucic2, Hartmut Döhner1, Konstanze Döhner1, Simone Fulda3,4,5,*, Lars Bullinger1,* 1Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany 2Early Discovery Biochemistry, Genentech, Inc., South San Francisco, CA, USA 3Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Germany 4German Cancer Consortium (DKTK), Heidelberg, Germany 5German Cancer Research Center (DKFZ), Heidelberg, Germany *Shared senior authorship Correspondence to: Lars Bullinger, email: [email protected] Simone Fulda, email: [email protected] Keywords: smac mimetic, IAP proteins, apoptosis, acute myeloid leukemia (AML), gene expression profiling (GEP) Received: March 31, 2016 Accepted: June 13, 2016 Published: July 02, 2016 ABSTRACT Apoptosis is deregulated in most, if not all, cancers, including hematological malignancies. Smac mimetics that antagonize Inhibitor of Apoptosis (IAP) proteins have so far largely been investigated in acute myeloid leukemia (AML) cell lines; however, little is yet known on the therapeutic potential of Smac mimetics in primary AML samples. In this study, we therefore investigated the antileukemic activity of the Smac mimetic BV6 in diagnostic samples of 67 adult AML patients and correlated the response to clinical, cytogenetic and molecular markers and gene expression profiles. Treatment with cytarabine (ara-C) was used as a standard chemotherapeutic agent. Interestingly, about half (51%) of primary AML samples are sensitive to BV6 and 21% intermediate responsive, while 28% are resistant. -
View Open Access the Biology of the Ets1 Proto-Oncogene Jürgen Dittmer*
Molecular Cancer BioMed Central Review Open Access The Biology of the Ets1 Proto-Oncogene Jürgen Dittmer* Address: Universität Halle-Wittenberg Universitätsklinik und Poliklinik für Gynäkologie Magdeburger Str. 24 06097 Halle (Saale) Germany Email: Jürgen Dittmer* - [email protected] * Corresponding author Published: 20 August 2003 Received: 21 July 2003 Accepted: 20 August 2003 Molecular Cancer 2003, 2:29 This article is available from: http://www.molecular-cancer.com/content/2/1/29 © 2003 Dittmer; licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. Abstract The Ets1 proto-oncoprotein is a member of the Ets family of transcription factors that share a unique DNA binding domain, the Ets domain. The DNA binding activity of Ets1 is controlled by kinases and transcription factors. Some transcription factors, such as AML-1, regulate Ets1 by targeting its autoinhibitory module. Others, such as Pax-5, alter Ets1 DNA binding properties. Ets1 harbors two phosphorylation sites, threonine-38 and an array of serines within the exon VII domain. Phosphorylation of threonine-38 by ERK1/2 activates Ets1, whereas phosphorylation of the exon VII domain by CaMKII or MLCK inhibits Ets1 DNA binding activity. Ets1 is expressed by numerous cell types. In haemotopoietic cells, it contributes to the regulation of cellular differentiation. In a variety of other cells, including endothelial cells, vascular smooth muscle cells and epithelial cancer cells, Ets1 promotes invasive behavior. Regulation of MMP1, MMP3, MMP9 and uPA as well as of VEGF and VEGF receptor gene expression has been ascribed to Ets1. -
Integrated Computational Approach to the Analysis of RNA-Seq Data Reveals New Transcriptional Regulators of Psoriasis
OPEN Experimental & Molecular Medicine (2016) 48, e268; doi:10.1038/emm.2016.97 & 2016 KSBMB. All rights reserved 2092-6413/16 www.nature.com/emm ORIGINAL ARTICLE Integrated computational approach to the analysis of RNA-seq data reveals new transcriptional regulators of psoriasis Alena Zolotarenko1, Evgeny Chekalin1, Alexandre Mesentsev1, Ludmila Kiseleva2, Elena Gribanova2, Rohini Mehta3, Ancha Baranova3,4,5,6, Tatiana V Tatarinova6,7,8, Eleonora S Piruzian1 and Sergey Bruskin1,5 Psoriasis is a common inflammatory skin disease with complex etiology and chronic progression. To provide novel insights into the regulatory molecular mechanisms of the disease, we performed RNA sequencing analysis of 14 pairs of skin samples collected from patients with psoriasis. Subsequent pathway analysis and extraction of the transcriptional regulators governing psoriasis-associated pathways was executed using a combination of the MetaCore Interactome enrichment tool and the cisExpress algorithm, followed by comparison to a set of previously described psoriasis response elements. A comparative approach allowed us to identify 42 core transcriptional regulators of the disease associated with inflammation (NFκB, IRF9, JUN, FOS, SRF), the activity of T cells in psoriatic lesions (STAT6, FOXP3, NFATC2, GATA3, TCF7, RUNX1), the hyper- proliferation and migration of keratinocytes (JUN, FOS, NFIB, TFAP2A, TFAP2C) and lipid metabolism (TFAP2, RARA, VDR). In addition to the core regulators, we identified 38 transcription factors previously not associated with the disease that can clarify the pathogenesis of psoriasis. To illustrate these findings, we analyzed the regulatory role of one of the identified transcription factors (TFs), FOXA1. Using ChIP-seq and RNA-seq data, we concluded that the atypical expression of the FOXA1 TF is an important player in the disease as it inhibits the maturation of naive T cells into the (CD4+FOXA1+CD47+CD69+PD-L1(hi) FOXP3 − ) regulatory T cell subpopulation, therefore contributing to the development of psoriatic skin lesions. -
RUNX1 Meets MLL: Epigenetic Regulation of Hematopoiesis by Two Leukemia Genes
Leukemia (2013) 27, 1793–1802 & 2013 Macmillan Publishers Limited All rights reserved 0887-6924/13 www.nature.com/leu SPOTLIGHT REVIEW RUNX1 meets MLL: epigenetic regulation of hematopoiesis by two leukemia genes CP Koh1,6, CQ Wang1,2,6, CEL Ng1,YIto1,2, M Araki1, V Tergaonkar2, G Huang3 and M Osato1,2,4,5 A broad range of human leukemias carries RUNX1 and MLL genetic alterations. Despite such widespread involvements, the relationship between RUNX1 and MLL has never been appreciated. Recently, we showed that RUNX1 physically and functionally interacts with MLL, thereby regulating the epigenetic status of critical cis-regulatory elements for hematopoietic genes. This newly unveiled interaction between the two most prevalent leukemia genes has solved a long-standing conundrum: leukemia-associated RUNX1 N-terminal point mutants that exhibit no obvious functional abnormalities in classical assays for the assessment of transcriptional activities. These mutants turned out to be defective in MLL interaction and subsequent epigenetic modifications that can be examined by the histone-modification status of cis-regulatory elements in the target genes. RUNX1/MLL binding confirms the importance of RUNX1 function as an epigenetic regulator. Recent studies employing next-generation sequencing on human hematological malignancies identified a plethora of mutations in epigenetic regulator genes. These new findings would enhance our understanding on the mechanistic basis for leukemia development and may provide a novel direction for therapeutic applications. This review summarizes the current knowledge about the epigenetic regulation of normal and malignant hematopoiesis by RUNX1 and MLL. Leukemia (2013) 27, 1793–1802; doi:10.1038/leu.2013.200 Keywords: RUNX1; AML1; MLL; epigenetic regulation INTRODUCTION Heterodimerization of RUNX1 with its partner b subunit RUNX1 and MLL are the two major genes that are frequently facilitates the DNA binding of RUNX1 in an allosteric manner altered in B33 and 19% of human acute leukemias, respectively.1–3 at the regulatory regions of target genes. -
Studies on the Core Binding Fa.Pdf
Studies on the Core Binding Factor Complex in Patients with Acute Myeloid Leukaemia Stephen Eirian Langabeer A thesis submitted to the University of London for the degree of Doctor of Philosophy 2002 Department of Haematology University College London 98 Chenies Mews London WCIE 6HX ProQuest Number: 10014981 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest 10014981 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Abstract The core binding factor (CBF) transcription factor complex is involved in the regulation of a number of genes essential for normal haemopoiesis. The complex is comprised of two subunits: the DNA-binding a subunit AMLl (CBFA2/RUNX1) and the p subunit CBFB, which interacts with AMLl to increase DNA binding. The AMLl and the CBFB genes are known to be disrupted in up to 25% of cases of acute myeloid leukaemia (AML). Therefore, in this thesis, several aspects of CBF leukaemia were investigated at the DNA and RNA level. The chromosomal abnormalities t(8;21)(q22;q22) and inv(16) (pl3q22) result in the creation of AMLl-ETO and CBFB-MYHll transcriptionally active fusion genes, and are associated with the M2 and M4Eo AML FAB types respectively. -
Novel Mechanisms of Transcriptional Regulation by Leukemia Fusion Proteins
Novel mechanisms of transcriptional regulation by leukemia fusion proteins A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the Department of Cancer and Cell Biology of the College of Medicine by Chien-Hung Gow M.S. Columbia University, New York M.D. Our Lady of Fatima University B.S. National Yang Ming University Dissertation Committee: Jinsong Zhang, Ph.D. Robert Brackenbury, Ph.D. Sohaib Khan, Ph.D. (Chair) Peter Stambrook, Ph.D. Song-Tao Liu, Ph.D. ABSTRACT Transcription factors and chromatin structure are master regulators of homeostasis during hematopoiesis. Regulatory genes for each stage of hematopoiesis are activated or silenced in a precise, finely tuned manner. Many leukemia fusion proteins are produced by chromosomal translocations that interrupt important transcription factors and disrupt these regulatory processes. Leukemia fusion proteins E2A-Pbx1 and AML1-ETO involve normal function transcription factor E2A, resulting in two distinct types of leukemia: E2A-Pbx1 t(1;19) acute lymphoblastic leukemia (ALL) and AML1-ETO t(8;21) acute myeloid leukemia (AML). E2A, a member of the E-protein family of transcription factors, is a key regulator in hematopoiesis that recruits coactivators or corepressors in a mutually exclusive fashion to regulate its direct target genes. In t(1;19) ALL, the E2A portion of E2A-Pbx1 mediates a robust transcriptional activation; however, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) AML and ETO-2 in hematopoietic cells. -
Core-Binding Factor Acute Myeloid Leukemia in Pediatric Patients Enrolled in the AIEOP AML 2002/01 Trial: Screening and Prognostic Impact of C-KIT Mutations
Letters to the Editor 1132 Core-binding factor acute myeloid leukemia in pediatric patients enrolled in the AIEOP AML 2002/01 trial: screening and prognostic impact of c-KIT mutations Leukemia (2014) 28, 1132–1134; doi:10.1038/leu.2013.339 t(16;16)(p13;q22) CBFB-MYH11. Screening for mutations of c-KIT was performed on cDNA by PCR amplification followed by Sanger sequencing of exons 8 and 17 or analysis by the Genescan and Genemapper software (Applied Biosystems Inc., Foster City, CA, The proto-oncogene c-KIT, which encodes a receptor for USA) for exon 11. The primers used are listed in Supplementary stem cell factor (SCF), belongs to the type-III receptor of the Table 1S. Denaturing, annealing and extension steps were tyrosine kinase subfamily and is characterized by five extracellular performed at 95 1C for 30 s, 60 1C for 30 s, 72 1C for 30 s, immunoglobulin-like domains, a single transmembrane helix (TM), respectively, for a total of 40 cycles on a thermocycler. PCR a cytoplasmic juxtamembrane domain(JMD), and a kinase products were resolved on a 2% agarose gel. After visual domain. Abnormal activation of c-KIT/SCF growth signal has been confirmation of amplification, 4 ml of PCR products of exon 8 or frequently documented to occur in cancers, including hematolo- 17 were purified with a mixture of 0.5 ml Exonuclease I and 1 mlof gical malignancies, and has been frequently associated with FastAP Thermosensitive Alkaline Phosphatase (Thermo Scientific, poor prognosis in adults with acute myeloid leukemia (AML) Milan, Italy) and analyzed by bidirectional sequencing on an harboring aberrancies at core-binding factor genes (CBF).1–3 ABI310 sequencer, using the BigDye terminator kit v3.1 (Applied c-KIT mutations have been reported in pediatric CBF-rearranged Biosystems Inc.). -
Identification of Genomic Targets of Krüppel-Like Factor 9 in Mouse Hippocampal
Identification of Genomic Targets of Krüppel-like Factor 9 in Mouse Hippocampal Neurons: Evidence for a role in modulating peripheral circadian clocks by Joseph R. Knoedler A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Neuroscience) in the University of Michigan 2016 Doctoral Committee: Professor Robert J. Denver, Chair Professor Daniel Goldman Professor Diane Robins Professor Audrey Seasholtz Associate Professor Bing Ye ©Joseph R. Knoedler All Rights Reserved 2016 To my parents, who never once questioned my decision to become the other kind of doctor, And to Lucy, who has pushed me to be a better person from day one. ii Acknowledgements I have a huge number of people to thank for having made it to this point, so in no particular order: -I would like to thank my adviser, Dr. Robert J. Denver, for his guidance, encouragement, and patience over the last seven years; his mentorship has been indispensable for my growth as a scientist -I would also like to thank my committee members, Drs. Audrey Seasholtz, Dan Goldman, Diane Robins and Bing Ye, for their constructive feedback and their willingness to meet in a frequently cold, windowless room across campus from where they work -I am hugely indebted to Pia Bagamasbad and Yasuhiro Kyono for teaching me almost everything I know about molecular biology and bioinformatics, and to Arasakumar Subramani for his tireless work during the home stretch to my dissertation -I am grateful for the Neuroscience Program leadership and staff, in particular