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Messenger‐RNA Networks in B‐Cell Chronic Lymphocytic Leukemia

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Messenger‐RNA Networks in B‐Cell Chronic Lymphocytic Leukemia Dissertation submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto‐Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences Elucidation of regulatory micro‐RNA/ messenger‐RNA networks in B‐cell chronic lymphocytic leukemia and mantle cell lymphoma presented by Diplom‐Biologe Jan Meier born in Berlin Heidelberg, 2012 Submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto‐Carola University of Heidelberg, Germany: May 29, 2012 Referees: PD Dr. Stefan Wiemann Prof. Dr. Peter Lichter Day of the oral examination: The investigations of the following dissertation were performed from December 2007 till May 2012 under supervision of Prof. Dr. Peter Lichter, Dr. Martina Seiffert and Dr. Armin Pscherer in the division of molecular genetics at the German Cancer Research Center (DKFZ), Heidelberg, Germany. Publications Ernst A, Campos B, Meier J, Devens F, Liesenberg F, Wolter M, Reifenberger G, Herold‐ Mende C, Lichter P, Radlwimmer B; “De‐repression of CTGF via the miR‐17‐92 cluster upon differentiation of human glioblastoma spheroid cultures”; Oncogne; 2010 Lössner C, Meier J, Warnken U, Rogers MA, Lichter P, Pscherer A, Schnölzer M; “Quantitative proteomics identify novel miR‐155 target proteins”; PloS one; 2011 Meier J, Hovestadt V, Zapatka M, Pscherer A, Lichter P, Seiffert M; “Genome‐wide identification of miR‐155 target genes and disproportionally AGO2‐associated miRNAs, including miR‐155, using RIP‐Seq”; manuscript in preparation Declarations I hereby declare that I have written the submitted dissertation “Elucidation of regulatory micro‐RNA/ messenger‐RNA networks in B‐cell chronic lymphocytic leukemia and mantle cell lymphoma” myself and in this process have used no other sources or materials than those expressly indicated. I hereby declare that I have not applied to be examined at any other institution, nor have I used the dissertation in this or any other form at any other institution as an examination paper, nor submitted it to any other faculty as a dissertation. Place, Date Jan Meier To Juliane & my family Table of contents Table of Contents ABBREVIATIONS ........................................................................................................................................... IV SUMMARY ........................................................................................................................................................ VI ZUSAMMENFASSUNG ................................................................................................................................ VIII 1 INTRODUCTION ..................................................................................................................................... 1 1.1 CANCER ................................................................................................................................................................. 1 1.1.1 The Development of cancer ....................................................................................................................... 1 1.2 B‐CELL NEOPLASMS ............................................................................................................................................ 4 1.2.1 Human B­cell lymphomas .......................................................................................................................... 5 1.3 B‐CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) ...................................................................................... 7 1.4 MANTLE CELL LYMPHOMA (MCL) ............................................................................................................... 11 1.5 NON‐CODING RNAS ........................................................................................................................................ 13 1.6 MICRORNAS ..................................................................................................................................................... 14 1.6.1 MicroRNA biogenesis ................................................................................................................................ 15 1.6.2 Operating principles of microRNAs .................................................................................................... 19 1.6.3 MicroRNAs and cancer ............................................................................................................................. 21 1.6.4 MicroRNA­155 .............................................................................................................................................. 22 1.6.5 The microRNA cluster miR­17­92 ........................................................................................................ 22 1.7 AIM OF THE STUDY .......................................................................................................................................... 23 2 MATERIAL AND METHODS .............................................................................................................. 25 2.1 MATERIAL ......................................................................................................................................................... 25 2.1.1 Chemicals ....................................................................................................................................................... 25 2.1.2 Enzymes .......................................................................................................................................................... 26 2.1.3 Kits ..................................................................................................................................................................... 26 2.1.4 Other consumables ..................................................................................................................................... 27 2.1.5 Solutions ......................................................................................................................................................... 28 2.1.6 Vectors ............................................................................................................................................................. 30 2.1.7 Primer .............................................................................................................................................................. 30 2.1.8 Small RNAs ..................................................................................................................................................... 33 2.1.9 Antibodies ...................................................................................................................................................... 34 2.1.10 Cell culture ............................................................................................................................................... 34 2.1.11 Instruments .............................................................................................................................................. 35 2.1.12 Software .................................................................................................................................................... 36 I Table of contents 2.1.13 Web­based microRNA target prediction tools ......................................................................... 36 2.1.14 Tools and Algorithms for high throughput sequencing analysis ..................................... 37 2.2 METHODS .......................................................................................................................................................... 37 2.2.1 Cell culture ..................................................................................................................................................... 37 2.2.2 Transfection methods ............................................................................................................................... 38 2.2.3 General molecular biology techniques .............................................................................................. 39 2.2.4 Cloning ............................................................................................................................................................. 42 2.2.5 Quantitative Real­Time Reverse Transcription PCR (qRT­PCR) ............................................ 43 2.2.6 Protein analysis ........................................................................................................................................... 45 2.2.7 MicroRNA related analyses .................................................................................................................... 47 2.2.8 Co­Immunoprecipitation of RNAs bound to AGO2 ....................................................................... 49 2.2.9 Next generation sequencing (Illumina) ............................................................................................ 50 2.2.10 Functional analyses .............................................................................................................................. 52 3 RESULTS ................................................................................................................................................ 53 3.1 EXPRESSION OF MIR‐155 AND MIR‐17‐92 IN PRIMARY CLL AND MCL CELLS .................................. 53 3.2 IDENTIFICATION OF MIRNA TARGET GENES IN CLL AND MCL
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