cam a22 7 4500 316997455 CHVBK 20201015055813.0 cr ## ######## 140620s2014 sz sm 00 0 eng d oai:infoscience.epfl.ch:198795 urn:nbn:ch:bel-epfl-thesis6211-1 urn 10.5075/epfl-thesis-6211 doi (SNL)991017980977303976 (NEBIS)010146714 (Sz)991017980977303976 (Sz)001871287 Sz ger rda 570 23sdnb Wirth Silvia 1985- (DE-588)1116570475 Verfasser aut Assessing the role of Hes1 and identification of target genes in human and murine T-ALL Silvia Wirth Lausanne 2014 1 Online-Ressource Thèse no 6211 EPF Lausanne, 2014 application/pdf The Notch signalling pathway is an ancient cell signalling mechanism that enables short-range communications between cells and controls a broad spectrum of cell fates and developmental processes. In the haematopoietic system Notch signalling has been linked to physiological, but also to pathological phenotypes of T cell development. Identification of numerous activating mutations within the NOTCH1 receptor in human T cell acute lymphoblastic leukaemia (T-ALL) patient samples demonstrated that aberrant activation of this signalling pathway is a frequent event in T-ALL. Active Notch signalling leads to the expression of a plethora of genes that might be drivers or passengers in tumorigenesis including Hes1, which encodes a transcriptional repressor. We have therefore studied Hes1 in the context of T-ALL in mouse models that mimic human disease and in human T-ALL cell lines with the aim to evaluate whether Hes1 affects disease development and disease maintenance and to characterize its function on a molecular level. The first part of this study is dedicated to the functional characterisation of Hes1 in vivo in T-ALL mouse models and in vitro in human T-ALL cell lines. Using a retroviral bone marrow transplant model of T-ALL in which progenitor cells are transduced with a retrovirus expressing constitutive active Notch1 intracellular domain (NICD) we could show that Hes1 is not required in established, late stage T-ALL cells, but that it promotes tumour progression in the early stages of the disease. We have also investigated the function of HES1 in human T-ALL and can show that the overexpression of dominant negative versions of Hes1 in two patient derived cell lines (T-ALL1, CUTLL-1) does not affect proliferation or apoptosis, emphasising that HES1 does not affect cell viability once cells are fully transformed to the leukemic state. In the second part of the study we set out to systematically delineate the gene regulatory networks down-stream of Hes1 by combining RNA-seq and ChIP-seq analysis. Comparing the gene expression of murine premalignant, early stage NICD induced CD4+CD8+ DP cells in the presence and absence of Hes1 by RNA-seq, we unexpectedly found a predominant upregulation of genes in cells expressing Hes1 indicating that Hes1 might rather act as a positive regulator of transcription than as a transcriptional repressor of distinct target genes. Hes1 might influence transcription through secondary or indirect effects as combinatorial analysis of RNA-seq and ChIP-seq led to the identification of only a small number of potential direct target genes that are transcriptionally regulated by Hes1. In summary, the role of Hes1 in promoting the early stages of the disease appears to be highly complex and is likely to involve both direct and indirect control of gene regulatory networks. CYTOLOGISCHE ASPEKTE DER SIGNALTRANSDUKTION UND SIGNALVERARBEITUNG (BIOKOMMUNIKATION) ger (ETHUDK)000021653 ethudk GENREGULATION, REGULATION DER GENEXPRESSION (MOLEKULARBIOLOGIE) ger (ETHUDK)000022879 ethudk LEUKÄMIE (PATHOLOGIE) ger (ETHUDK)000027146 ethudk T-LYMPHOZYTEN (BLUTZELLEN) ger (ETHUDK)000038601 ethudk TIERISCHE MODELLE IN DER MEDIZIN ger (ETHUDK)000056362 ethudk Hochschulschrift (DE-588)4113937-9 gnd-content Hochschulschrift gnd-content xehelv xediss 2017 570 snl ehelv sb 2017/26 570 snl-sb u CYTOLOGISCHE ASPEKTE DER SIGNALTRANSDUKTION UND SIGNALVERARBEITUNG (BIOKOMMUNIKATION) ger 57.016.3,1.047.6 nebis E1 u T-LYMPHOZYTEN (BLUTZELLEN) ger 612.112.94,2 nebis E1 u LEUKÄMIE (PATHOLOGIE) ger 616.155.392 nebis E1 u GENREGULATION, REGULATION DER GENEXPRESSION (MOLEKULARBIOLOGIE) ger 577.218,1 nebis E1 u TIERISCHE MODELLE IN DER MEDIZIN ger 61.001.575'59 nebis E1 u ASPECTS CYTOLOGIQUES DE LA TRANSMISSION ET DU TRAITEMENT DES SIGNAUX (BIOCOMMUNICATION) fre 57.016.3,1.047.6 nebis E1 u CYTOLOGICAL ASPECTS OF SIGNAL TRANSDUCTION AND SIGNAL PROCESSING (BIOCOMMUNICATION) eng 57.016.3,1.047.6 nebis E1 u T LYMPHOCYTES (BLOOD CELLS) eng 612.112.94,2 nebis E1 u LYMPHOCYTES T (CELLULES SANGUINES) fre 612.112.94,2 nebis E1 u LEUCÉMIE (PATHOLOGIE) fre 616.155.392 nebis E1 u LEUKAEMIA (PATHOLOGY) eng 616.155.392 nebis E1 u GENE REGULATION, REGULATION OF GENE-EXPRESSION (MOLECULAR BIOLOGY) eng 577.218,1 nebis E1 u RÉGULATION DES GÈNES ET DE L'EXPRESSION DES GÈNES (BIOLOGIE MOLÉCULAIRE) fre 577.218,1 nebis E1 u MODÈLES ANIMAUX EN MÉDECINE fre 61.001.575'59 nebis E1 u ANIMAL MODELS IN MEDICINE eng 61.001.575'59 nebis E1 École polytechnique fédérale de Lausanne (DE-588)1003500-X Grad-verleihende Institution dgg SNL NB001 NB999 - chb99 - Record https://infoscience.epfl.ch/record/198795 Thesis https://infoscience.epfl.ch/record/198795/files/EPFL_TH6211.pdf URN https://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:bel-epfl-thesis6211-1 http://www.e-helvetica.nb.admin.ch/directAccess?callnumber=bel-epfl-thesis6211-1 BK020353 XK020053 XK020000 1 Hochschulschrift = Thèse/Mémoire 2 CF Elektron. Daten Fernzugriff=Fichier online EPF nebis E2 e-library 2014 these nebis EC 033 E01-20140707 NEBIS E16 E16 RH HB 16905 NEBIS E02 E02 E02SP ZTH 6211 SNL 100 1- Wirth Silvia 1985- (DE-588)1116570475 Verfasser aut SNL 710 2- École polytechnique fédérale de Lausanne (DE-588)1003500-X Grad-verleihende Institution dgg SNL 856 40 Record https://infoscience.epfl.ch/record/198795 SNL 856 40 Thesis https://infoscience.epfl.ch/record/198795/files/EPFL_TH6211.pdf SNL 856 4- URN https://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:bel-epfl-thesis6211-1 SNL 856 42 http://www.e-helvetica.nb.admin.ch/directAccess?callnumber=bel-epfl-thesis6211-1 NEBIS 700 1- Wirth Silvia NEBIS 700 1- Radtke Freddy 1964- (DE-588)1089475136 Akademischer Betreuer dgs NEBIS 856 -- https://dx.doi.org/10.5075/epfl-thesis-6211 Online via EPFL E-Library E02 SWISSBIB 316997455 ORANGE 316997455