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Symbol- Und Abkürzungsverzeichnis Untersuchung des Beitrags von ETV6/RUNX1 zur Entstehung akuter lymphatischer Leukämie (ALL) im Kindesalter Inauguraldissertation zur Erlangung des Grades eines Doktors der Naturwissenschaften (Dr. rer. nat.) im Fachbereich Biologie, Chemie und Pharmazie der Freien Universität Berlin vorgelegt von Kerstin Hasse Berlin, Dezember 2012 1. Gutachter: Prof. Hartmut Oschkinat Forschungsinstitut für Molekulare Pharmakologie, Berlin 2. Gutachter: Prof. Burghardt Wittig Institut für Molekularbiologie und Bioinformatik der FU Berlin Tag der Disputation: 19. November 2012 Inhaltsverzeichnis Symbol- und Abkürzungsverzeichnis ...................................................I 1. Einleitung und Zielsetzung ................................................................1 1.1. Leukämien ................................................................................................... 1 1.2. ALL im Kindesalter....................................................................................... 2 1.2.1. Immunphänotypen der ALL........................................................... 3 1.2.2. Zytogenetische und molekulargenetische Veränderungen bei ALL ...................................................................................................... 4 1.3. Molekulare Pathogenese von Leukämien.................................................... 7 1.4. Die Transkriptionsfaktoren ETV6 und RUNX1 ............................................. 8 1.4.1. Transkriptionsfaktor ETV6............................................................. 8 1.4.1.1. Genstruktur von ETV6................................................................... 8 1.4.1.2. ETV6-Protein und Funktion........................................................... 9 1.4.1.3. Veränderung von ETV6 bei Leukämien ...................................... 12 1.4.2. Transkriptionsfaktor RUNX1 ....................................................... 14 1.4.2.1. Genstruktur von RUNX1 ............................................................. 14 1.4.2.2. RUNX1-Protein und Funktion...................................................... 15 1.4.2.3. Veränderung von RUNX1 bei Leukämien ................................... 19 1.5. Der chimäre Transkriptionsfaktor ETV6/RUNX1........................................ 21 1.5.1. Fusionsgen ETV6/RUNX1 .......................................................... 21 1.5.2. ETV6/RUNX1-Fusionsprotein ..................................................... 22 1.5.3. Funktion und Einfluss von ETV6/RUNX1 auf Leukämien............ 23 1.6. t(12;21) bei ALL im Kindesalter.................................................................. 25 1.7. Fragestellung und Zielsetzung................................................................... 26 2. Material und Methoden.....................................................................28 2.1. Material...................................................................................................... 28 2.1.1. Chemikalien und Verbrauchsmaterialien..................................... 28 2.1.2. Bakterienstämme und Zelllinien .................................................. 28 2.1.3. Medien und Agarplatten für E. coli .............................................. 29 2.1.4. Plasmidvektoren ......................................................................... 30 2.1.5. Antikörper und Antiseren............................................................. 31 2.2. Molekularbiologische Techniken................................................................ 31 2.2.1. Anzucht von E. coli Bakterienkulturen......................................... 31 2.2.2. Methoden zur Isolierung von DNA .............................................. 32 2.2.2.1. Plasmidisolierung mit dem QIAprep Spin Miniprep Kit................ 32 2.2.2.2. Plasmidisolierung mit dem JetStar Kit von Genomed ................. 32 2.2.2.3. Isolierung genomischer DNA mit dem Generation Capture Column Kit von Qiagen ............................................................................ 32 2.2.3. Amplifizierung von DNA durch Polymerase-Ketten-Reaktion (PCR) .................................................................................................... 32 2.2.4. Aufreinigung von PCR-Fragmenten ............................................ 33 2.2.5. Real time quantitative PCR ......................................................... 33 2.2.6. Auftrennung von Nukleinsäuren durch horizontale Agarose- Gelelektrophorese....................................................................... 35 2.2.7. Klonierung von DNA-Fragmenten ............................................... 35 2.2.7.1. In-Fusion-PCR-Klonierung .......................................................... 35 2.2.7.2. Creator-Rekombination ............................................................... 37 2.2.8. Das Creator-kompatible onkoretrovirale Vektorsystem RevTet-ON .................................................................................................... 39 2.2.9. Transformation............................................................................ 40 2.2.10. Spezifische Spaltung von DNA mit Restriktionsendonukleasen.. 40 2.2.11. DNA-Sequenzierung ................................................................... 40 2.2.11.1. Sequenzierreaktion ..................................................................... 40 2.2.11.2. Aufreinigung der Sequenzierreaktion.......................................... 41 2.2.11.3. Acrylamid-Gelelektrophorese zur Sequenzierung....................... 41 2.2.12. Präparation von RNA .................................................................. 41 2.2.12.1. Präparation von Gesamt-RNA .................................................... 41 2.2.12.2. Präparation Gesamt- und micro RNA.......................................... 41 2.2.13. cDNA-Erststrangsynthese durch Reverse Transkription............. 42 2.2.14. Quantifizierung von Nukleinsäuren und Proteinen ...................... 42 2.2.14.1. Quantifizierung von Nukleinsäuren ............................................. 42 2.2.14.2. Quantifizierung von Proteinen..................................................... 43 2.2.15. Isolierung von Proteinen ............................................................. 43 2.2.16. Nachweis von Proteinen im Western Blot ................................... 45 2.2.16.1. SDS-Polyacrylamid-Gelelektrophorese....................................... 45 2.2.16.2. Proteintransfer auf PVDF-Membran............................................ 46 2.2.16.3. Immunfärbung............................................................................. 46 2.3. Zellkultur / Heterologe Expression ............................................................. 47 2.3.1. Kultivierung der Zellen ................................................................ 47 2.3.2. Transiente Transfektion .............................................................. 48 2.3.3. Selektion stabiler Zellen .............................................................. 49 2.3.4. Reinigung vitaler Zellen mit Ficoll-Dichtegradientenzentrifugation .................................................................................................... 50 2.3.5. Beschichtung von Zellkulturplatten mit Retronectin .................... 50 2.3.6. Infektion von Zielzellen................................................................ 50 2.3.6.1. Produktion und Aufreinigung der Viren ....................................... 51 2.3.6.2. Infektion adhärenter Zellen ......................................................... 51 2.3.6.3. Infektion von Suspensionszellen in Retronectin-beschichteten Zellkulturplatten........................................................................... 51 2.3.6.4. Ko-Kultur von PT67 und BaF3 .................................................... 52 2.3.6.5. Infektion im 96-Well-Format ........................................................ 52 2.3.7. Isolierung von Klonen durch limitierte Verdünnung der Zellen .... 52 2.4. Zellbiologische Methoden .......................................................................... 53 2.4.1. Proliferations- und Zytotoxizitätsmessung mit dem MTS-Assay .53 2.4.2. Apoptose- und Nekrosedetektion mittels Annexin V-Markierung und Propidiumiodidfärbung ......................................................... 54 2.4.3. Analyse der Zellzyklusverteilung mittels Propidiumiodidfärbung.54 2.4.4. Durchflusszytometrische Analyse von Zelloberflächenproteinen 54 2.4.5. Quantifizierung sekretierter Proteine mittels Sandwich-ELISA.... 55 2.5. Genexpressionsanalyse mit Oligonukleotidarrays ..................................... 55 2.5.1. cDNA-Synthese, Hybridisierung und Fluoreszenzdetektion........ 55 2.5.2. Statistische Auswertung.............................................................. 56 2.5.3. Analyse von Bindungsstellen für Transkriptionsfaktoren............. 57 2.6. Proteomanalyse......................................................................................... 58 2.6.1. 2D-Gelelektrophorese................................................................. 58 2.6.1.1. Isoelektrische Fokussierung........................................................ 58 2.6.1.2. SDS-PAGE ................................................................................. 59 2.6.1.3. Silberfärbung............................................................................... 59 2.6.2. Quantifizierung der Proteinspots mit Delta2D ............................. 60 2.6.3. Identifizierung der Proteine mittels MALDI-TOF.......................... 60 2.6.4.
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