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KI Mouse Models, Interferon-Α Therapy and Clonal Architecture

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KI Mouse Models, Interferon-Α Therapy and Clonal Architecture UNIVERSITE PARIS-SUD ÉCOLE DOCTORALE : Cancérologie Laboratoire : INSERM U1009 Hématopoïèse Normales et pathologiques DISCIPLINE Cancérologie THÈSE DE DOCTORAT Soutenue le 27/11/2013 par Salma HASAN JAK2V617F-positive Myeloproliferative Neoplasms: KI mouse models, interferon-α therapy and clonal architecture Directeur de thèse : Dr. Jean-Luc VILLEVAL (DR2-INSERM U1009, IGR, Villejuif) Composition du jury : Président du jury : Dr. Sandra PELLEGRINI (DR2-CNRS-Institut Pasteur, Paris) Rapporteurs : Dr. Chloé JAMES (AHU CHU-INSERM U1034, Bordeaux) Pr. Radek SKODA (Professeur-University Hospital Basel, Suisse) Examinateurs : Pr. Christian AUCLAIR (Professeur-ENS Cachan) Pr. Stefan CONSTANTINESCU (Professeur-Ludwig Institute, Belgique) ‘Tis a common proof, That lowliness is young ambition’s ladder, Whereto the climber-upward turns His face … -William Shakespeare, Julius Caesar ACKNOWLEDGMENTS “Thankfulness brings you to the place where the Beloved lives” -Rumi Acknowledgments hough only my name appears on the cover of this dissertation, a major research project like this is never the work of anyone alone. It is a pleasure to convey my gratitude to these great many people, T who in their different ways, have made my graduate experience the one that I will cherish forever… I must, foremost, extend my acknowledgements to my thesis committee. I am grateful to Dr. Sandra Pellegrini for being the president of my thesis committee. I am thankful to Dr. Chloé James and Pr. Radek Skoda for, in the midst of all their activities, they accepted to be the reviewers of my dissertation. Equally, I am grateful to Pr. Christian Auclair and Pr. Stefan Constantinescu for their precious time they have generously allotted for my PhD defense being examiners. This jury in itself is a compliment for me! I owe my deepest gratitude to Pr. Eric Solary for accepting me in his lab. More than that, I appreciate your friendly, ever-welcoming and motivating attitude. I thank you for all the continuous help, discussions and guidance whenever I was in need. My sincere thanks to my PhD supervisor Dr. Jean-Luc Villeval! His guidance for the selection of final theme for this research and his thought-provoking and constructive criticism helped me to accomplish this journey. I wish one day I could reproduce your rational scientific thinking and skilled writing. I owe my profound gratitude to Dr. William Vainchenker for his unconditional support. Scientific discussions with you have triggered and nourished my intellectual maturity that I will benefit from, for a long time to come… Catherine Lacout I owe you a heart-felt gratitude for the uncountable things you have done for me without mention! Thanks for introducing me to the world of mice. Thanks a million for your practical advices, encouragement and moral support in day-to-day affairs during these long four years. Comment je vais faire sans toi Catherine ?! Thanks Isabele Plo! I cherished ‘The 46/1’ project… the way we tried to make people understand that 46/1 is not as boring/complicated as it appears! I feel obliged to give a special mention to Nathalie Droin for her generous help on IKAROS project and beyond. Thank you! I hope one day we will figure out the exact number of existing IKAROS isoforms on earth… I would like to extend my humble acknowledgments to Isabelle Godin: for making me discover le joli collier de perles, Hana, Fawzia, Najet, Yunhua, Monika: for generous donations of antibodies, Antonio, JPLC: for help with RT-PCR, Remi, François and Stephane who in one way or other played a role in my development as a scholar. Acknowledgments I think of Paule and Rahma for their help in administrative issues. Thank you Philippe and Yann for your help in realization of my colorful experiments. I am thankful to Dr. Patrick Gonin and his team for the animal care. It is a pleasure to convey my gratitude to the clinical sample collaborators: Dr. Nicole Casadevall, Dr. Jean Jacques Kiladjian, Dr. Bruno Cassinat, Dr. Michaela Fontenay, Dr. Christine Dosquet, Dr. Christine Chomienne and Fanny Fava. And also all the patients who have accepted to be a part of this study deserve a particular thanks. Thanks Iléana for being my best buddy in the lab and outside! Thanks Debeurme for sharing your optimism!! Your support! And also thanks for Prism, Flow Jo, ELISA… hein hein… Pr. Langlois, Joseph and Elodie deserve special mention for French lessons. Thanks Olivier (from copy/paste of an image… to cytometry problems… to the cloning of a construct), Céline, Pauline, Sofiane, Xenia, Sarah, Florence (pour les p’tits RDV convivial), Larissa, YanYan, Dominique, Caroline, Idinath, Nathalie B, Rudolph, Gaëlle, Marc, Aline M, Hind, Fabrizia, Barbara, Jane, Hajer, Hayat, Vladimir, Jia Jia, Hélène, Afaq, Emna, Siham, Kristell, Kahia, Aline B, Lise, Morgane, Alberta, Marie, Julien, Claudine and Niccolò. Thanks for all the good time we spent! Thanks Farooq for being the one with whom I could share my taste of poetry, readings, politics back home and more… Thanks Fayeza FK and Elia Shayan for your priceless friendship! Shariq (crazy outings!!), Jai and AQSW. Best of luck Dr. Beke! (Bientôt bientôt t’auras ton bureau.. ton l’ordinateur). Where would I be without my family? Mummy and Abbu, words fail to express how much gratitude I owe you! More than infinite!! Loads of prayers, constant concern and unconditional love… I have always evidenced an intangible presence of yours! Thanks Sara, Asif Bhai, Erum Apa, Naheed Bhabhi and Ali for encouraging me in all my persuits! My dearest kiddies Zerlush, Uroosa, Unsa and Murtajiz, thanks for being the reason to laugh! Zerlush, I hope one day I will satisfy all your curiosities about my life in France out of that little skype window… Thanks Adeeb for your love, affection and persistent confidence in me! Equally cheerful I thank everybody who was important to the successful realization of this dissertation, as well as expressing my apology that I could not mention personally one by one. To you my sincere acknowledgments! Present is the moment just passed… Acknowledgments Mummy & Abbu INDEX RESUME ................................................................................................................................................. 1 LIST OF FIGURES AND TABLES ..................................................................................................... 3 LIST OF ABBREVIATIONS ................................................................................................................ 6 INTRODUCTION ................................................................................................................................ 10 1. Hematopoiesis – an overview .................................................................................................................. 11 1.1. Definition ........................................................................................................................................... 11 1.2. Hematopoietic hierarchy ................................................................................................................... 11 1.3. Lineage selection – a guide to hematopoietic road map ................................................................... 12 1.4. Homeostasis - self renewal, cell cycle and apoptosis ........................................................................ 13 2. Myeloproliferative neoplasms ................................................................................................................ 14 2.1. Myeloid neoplasms ............................................................................................................................ 14 2.2. Classification – from the age of Dameshek to the epoch of genome ................................................. 14 2.3. Main etiological factors in MPN ....................................................................................................... 15 2.4. Classic Ph- MPNs .............................................................................................................................. 17 2.4.1. Main molecular characteristics of Ph- MPN .............................................................................. 17 2.4.1.1. Ph- MPNs are acquired clonal HSC disorders ................................................................... 17 2.4.1.2. Ph- MPNs are characterized by mature myeloid cell hyper proliferation .......................... 17 2.4.2. Main entities in Ph- MPN .......................................................................................................... 18 2.4.2.1. Essential thrombocythemia ................................................................................................ 18 2.4.2.2. Primary myelofibrosis ........................................................................................................ 20 3. The JAKV617F mutation ............................................................................................................................ 23 3.1. JAK2 as a signaling molecule ........................................................................................................... 23 3.1.1. JAK2 structure and cytokine receptor interaction ...................................................................... 23 3.1.2. Negative regulation of JAK2 signaling ...................................................................................... 25 3.1.3. Constitutive activation of JAK2 ................................................................................................
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