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Flt3 Receptor Tyrosine Kinase in AML and Its Modulation of the P53/Hdm2/Bcl-2 Pathway

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Flt3 Receptor Tyrosine Kinase in AML and Its Modulation of the P53/Hdm2/Bcl-2 Pathway View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by NORA - Norwegian Open Research Archives Flt3 receptor tyrosine kinase in AML and its modulation of the p53/Hdm2/Bcl-2 pathway Line Wergeland Dissertation for the degree philosophiae doctor (PhD) at the University of Bergen 2007 2 Scientific environment This work was performed at the Institute of Medicine, Hematology section, University of Bergen and was funded by the University of Bergen 3 Acknowledgements My sincere gratitude goes to my supervisor Bjørn Tore Gjertsen for introducing me to the field of Flt3 research. His never-ending enthusiasm, optimism and expert scientific advice has made the years in his lab very enjoyable. I am very grateful that he had belief in me and let me join his group. I also want to thank my co-supervisor Øystein Bruserud for all his help and support. I really appreciate that he always takes the time to answer my questions, read my manuscripts or get me some cells. All members of the Gjertsen-group, past and present, are thanked for the making of a very good working environment, and for being good colleagues and friends. Thanks to Nina, Gry, Emmet, Ingvild, Jørn, Maren, Ingeborg, Marianne, Kjetil, Lars Erik, Henriette, Therese, Siv Lise, Lena, Bjarte, Tony, Maja, Elisabeth, Rakel, Sigrun og Stein-Erik for friendship and discussions. I especially appreciate that Nina and Ingvild helped with the proof-reading of my thesis. Ingvild, Lena and Siv-Lise deserve special attention for the practical help in the lab. All the help I got from Linn Hodneland is also highly appreciated. My co-authors are all acknowledged for their contributions. I am especially grateful to Eystein Oveland and Randi Hovland for their experimental help and for fruitful discussions. All my colleagues at the Institute of Medicine are thanked for creating very enjoyable surroundings. Numerous discussions over coffee or lunch have been an important and pleasant diversion from science. I should have mentioned all your names, but the space is limited…… Thank you all :-) Finally I want to thank my family and friends for their encouragement and interest in my work. I am especially grateful to my daughter Mathea and my husband Torbjørn for their love and support. Bergen, July 2007 Line Wergeland 4 Table of contents ABBREVIATIONS.............................................................................................................................................5 SUMMARY .........................................................................................................................................................6 LIST OF PAPERS ..............................................................................................................................................7 1. INTRODUCTION ....................................................................................................................................8 1.1 ACUTE MYELOID LEUKEMIA..................................................................................................................8 Definition and classification.........................................................................................................................................8 Prognostic factors.......................................................................................................................................................11 Treatment....................................................................................................................................................................12 1.2 RECEPTOR TYROSINE KINASES CLASS III IN NORMAL HEMATOPOIESIS AND LEUKEMOGENESIS............15 1.3 FMS-LIKE TYROSINE KINASE 3 (FLT3) .................................................................................................16 Flt3 signaling..............................................................................................................................................................18 Flt3 and normal hematopoiesis ..................................................................................................................................20 Flt3 and leukemogenesis; internal tandem duplications and point mutations............................................................20 Flt3 and chemoresistance in human AML ..................................................................................................................22 1.4 THE P53/HDM2 PATHWAY ....................................................................................................................23 Human homologue of murine double minute 2 (Hdm2)..............................................................................................23 Hdm2 in regulation of p53..........................................................................................................................................23 p53 independent functions of Hdm2............................................................................................................................24 Hdm2 in AML .............................................................................................................................................................25 1.5 THE UBIQUITIN-PROTEASOME PATHWAY ..............................................................................................26 Protein degradation and regulation by ubiquitin conjugation....................................................................................26 E3 ubiquitin ligases ....................................................................................................................................................27 Functional role in AML ..............................................................................................................................................28 1.6 THE BCL-2 FAMILY OF PROTEINS..........................................................................................................28 Overview.....................................................................................................................................................................28 B-cell lymphoma gene 2 (Bcl-2) .................................................................................................................................29 Myeloid cell leukemia 1 (Mcl-1).................................................................................................................................29 Bcl-2 family members in AML ....................................................................................................................................29 2. AIMS OF THE STUDY .........................................................................................................................31 3. METHODOLOGICAL CONSIDERATIONS.....................................................................................32 3.1 CHOICE OF EXPERIMENTAL CELL MODEL ..............................................................................................32 AML cell lines versus primary AML cells...................................................................................................................32 3.2 PROTEIN QUANTIFICATION ...................................................................................................................33 Quantification in Western blots and by flow cytometry ..............................................................................................33 Intra- and extracellular flow cytometry......................................................................................................................34 3.3 IMMUNOPRECIPITATION........................................................................................................................36 Co-immunoprecipitation; determination of protein-protein interactions ...................................................................36 Alternatives to co-immunoprecipitation......................................................................................................................37 4. SUMMARY OF PAPERS......................................................................................................................39 4.1 PAPER I ................................................................................................................................................39 4.2 PAPER II ...............................................................................................................................................39 4.3 PAPER III..............................................................................................................................................40 4.4 PAPER IV..............................................................................................................................................41 5. GENERAL DISCUSSION .....................................................................................................................42 5.1 THE JUXTAMEMBRANE REGION OF FLT3...............................................................................................42 Sequence similarity of the RTK III family...................................................................................................................42 Importance of the juxtamembrane region...................................................................................................................43 Duplicated ubiquitin dependent endocytosis motif (UbE) ..........................................................................................45
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