Dokument: Genetic and Epigenetic Landscapes of Pediatric Acute Lymphoblastic Leukemia Subtypes
| Titel: | Genetic and Epigenetic Landscapes of Pediatric Acute Lymphoblastic Leukemia Subtypes | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=52036 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20200122-082937-9 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dörrenberg, Mareike [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Borkhardt, Arndt [Gutachter] Prof. Dr. Gohlke, Holger [Gutachter] | |||||||
| Stichwörter: | pediatric acute lymphoblastic leukemia, cancer, next generation sequencing | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibungen: | Akute lymphatische Leukämie ist eine maligne Krankheit des hämatopoetischen Systems. Je
nachdem welcher Zelltyp betroffen ist, wird die akute lymphatische Leukämie (ALL) in BZell- und T-Zell ALL eingeteilt. Beide Leukämietypen können in Subtypen unterteilt werden. Diese werden über genetische Veränderungen im Patientengenom definiert, die für die Tumorentstehung hauptverantwortlich sind. Ein Teilgebiet dieser Arbeit ist die Analyse von Unterschieden zwischen zwei Tumorsubtypen der B-Zell ALL. Der erste Subtyp wird durch eine Translokation der beiden Chromosomen 1 und 19 charakterisiert. Diese Translokation führt zu einem Fusionsprotein aus den beiden Transkriptionsfaktoren TCF3 und PBX1. Dieser leukämische Subtyp tritt häufig im Kindesalter auf und besitzt eine hohe Heilungschance. Der zweite Subtyp wird durch die Translokation der beiden Chromosomen 17 und 19 charakterisiert. Durch diese entsteht ein Fusionsprotein der beiden Transkriptionsfaktoren TCF3 und HLF. Dieser leukämische Subtyp kommt sehr selten vor und ist schwer zu behandeln. Ein weiterer Aspekt der Gruppierung von Leukämietypen ist das Alter der Patienten. Im Vergleich zu der Entstehung einer T-Zell Leukämie im Kindesalter, ist die Entstehung einer Leukämie im Säuglingsalter sehr selten. Kenntnisse über klinische und molekulare Grundlagen der T-Zell akuten lymphatischen Leukämie im Säuglingsalter ist kaum vorhanden. Außerdem ist nicht klar, ob eine T-Zell ALL im Säuglingsalter im Vergleich zur T-Zell ALL im Kindesalter ein eigenes Krankheitsbild darstellt. Daher beschäftigt sich das zweite Thema dieser Arbeit mit der Analyse von Unterschieden zwischen einer T-Zell ALL im Säuglings- und im Kindesalter. Für beide Analysen wurde Patientenmaterial auf einer Illuminaplattform sequenziert. Um differentiell exprimierte Gene und miRNAs zwischen den beiden B-Zell Leukämietypen zu erfassen, wurden verschiedene Filter der Datenanalyse-Pipeline verwendet. Eine Korrelationsanalyse sowie eine target prediction wurde durchgeführt, um potentielle mRNAmiRNA target-pairs zu entdecken, die jedoch in-vitro durch qPCR und einen Luciferase- Assay nicht validiert werden konnten. Mit miRDeep wurden potentielle neue miRNAs gefunden, die jedoch ebenfalls nicht durch qPCR und Northern blot validiert werden konnten. Anhand der Sequenzierdaten wurde aufgedeckt, dass hsa-miR-7847 in einigen Patienten mit t( 1;19) mutiert im Genom vorliegt, was zukünftig validiert werden wird. Ein neuer HDAC6 Inhibitor wurde an einer Zelllinie mit t(17;19) getestet. Dieses führte nachweislich zu einer Veränderung in der Genexpression. Um Unterschiede zwischen einer T-Zell-Leukämie im Säuglings- und im Kindesalter zu analysieren, wurde eine Exomsequenzierung durchgeführt. Dabei wurden Mutationen in den Genen NOTCH2, NOTCH3, PTEN und KRAS in den Säuglingspatienten gefunden. Die Analyse der Transkriptome zeigte 760 differentiell exprimierte Gene und 58 differentiell exprimierte miRNAs zwischen beiden Kohorten. Über eine Korrelationsanalyse und eine target prediction wurden 47 potentielle mRNA-miRNA target pairs gefunden, von denen die meisten einen Einfluss auf die Tumorentstehung haben. Eine pathway-Analyse deckte betroffene pathways in der Säuglings-T-Zell ALL auf, die im Zusammenhang mit Funktionen des Immunsystems und der Tumorentwicklung stehen, wie z.B. die Aktivierung des ERK5 pathways. Bei Analyse von t(1;19)- und t(17;19)-ALL konnten vorhergesagte Interaktionen zwischen mRNAs und miRNAs sowie das Vorhandensein potentiell neuer miRNAs durch Anwendung verschiedener molekularbiologischer widerlegt werden. Trotzdem wurden deutliche molekulare Merkmale in Transkription und Epigenom in der Säuglings-T-Zell Leukämie im Vergleich zur T-Zell Leukämie im Kindesalter entdeckt, welche einen potentiellen Einfluss auf die Entstehung und Entwicklung einer Säuglings-T-Zell Leukämie haben können.Acute lymphoblastic leukemia (ALL) is a malignant disease of the hematopoietic system. It is distinguished in B-cell- and T-cell acute lymphoblastic leukemia depending on the affected cell type. Both leukemic types can be further divided into subgroups regarding genetic aberrations, which occur in the leukemic genomes and are mainly responsible for tumor development. One aspect of this thesis is the analysis of differences between two of these tumor subtypes of B-cell ALL. The first subtype is characterized by a translocation between chromosomes 1 and 19, leading to a fusion of the two transcription factors TCF3 and PBX1. It is a frequently occurring leukemic subtype in childhood, inferring a good prognosis. The second subtype is characterized by a translocation between chromosomes 17 and 19, leading to a fusion of the two transcription factors TCF3 and HLF. This leukemic subtype is very rare and associated with a poor prognosis. Another aspect of leukemic grouping is the age of patients. Especially in T-cell ALL the development of leukemia in infancy is extremely rare compared to a development in childhood. Clinical and molecular knowledge about infant T-cell ALL is nearly lacking and it is not clear, if it represents a distinct disease compared to childhood T-cell ALL. Therefore, the second topic of this thesis deals with the analysis of differences between infant and childhood T-cell ALL. To address both topics, patient material was sequenced on an Illumina next generation sequencing platform. Different filter settings of the data analysis pipeline were used to detect differentially expressed genes and miRNAs between the two B-cell ALL subtypes. Correlation analysis and target prediction was performed to find potential mRNA-miRNA target pairs which, however, could not be validated in-vitro by qPCR and luciferase assay. Potential novel miRNAs were found using miRDeep, which –again- could not be validated by qPCR and Northern blot. Hsa-miR-7847 was found to be mutated in some t(1;19) patients, which has to be validated. A novel HDAC6 inhibitor was tested on a t(17;19) cell line, leading to differences in gene expression. Exome sequencing was performed to identify differences between infant and childhood T-cell ALL and mutations in NOTCH2, NOTCH3, PTEN and KRAS were detected in infant patients. Analysis of transcriptomes revealed 760 differentially expressed genes and 58 differentially expressed miRNAs between both cohorts. Correlation analysis and target prediction revealed 47 potential mRNA-miRNA target pairs of which the most have an impact on tumor development. A pathway analysis revealed affected pathways in infant patients, which rely on immune functions or tumorigenesis like the activation of the ERK5 pathway. In summary, predicted interactions between mRNAs and miRNAs as well as predicted novel miRNAs could be disproved by different techniques of molecular biology by analyzing t(1;19 )- and t(17;19) B-cell ALL. Nevertheless, we found distinct molecular features in infant compared to childhood T-cell ALL on a transcriptomic and epigenetic level, which have a potential impact on development and course of disease. | |||||||
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| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät | |||||||
| Dokument erstellt am: | 22.01.2020 | |||||||
| Dateien geändert am: | 22.01.2020 | |||||||
| Promotionsantrag am: | 11.09.2019 | |||||||
| Datum der Promotion: | 16.12.2020 |
