Role of the SUMO pathway in Acute Myeloid Leukemias response to treatments Hayeon Baik To cite this version: Hayeon Baik. Role of the SUMO pathway in Acute Myeloid Leukemias response to treatments. Human health and pathology. Université Montpellier, 2017. English. NNT : 2017MONTT016. tel-01680009 HAL Id: tel-01680009 https://tel.archives-ouvertes.fr/tel-01680009 Submitted on 10 Jan 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Délivré par l’Université de Montpellier Préparée au sein de l’école doctorale CBS2 Sciences Chimiques et Biologiques pour la Santé Et de l’unité de recherche IGMM CNRS UMR5535 Institut de Génétique Moléculaire de Montpellier Spécialité Biologie-Santé Présentée par Hayeon BAIK Role of the SUMO pathway in Acute Myeloid Leukemias response to treatments Soutenue le 29 Juin 2017 devant le jury composé de Dr. Valérie Lallemand-Breitenbach Rapporteur Directrice de Recherche, INSERM, Paris Président du jury Pr. Stefan Müller Rapporteur Professeur, Université de Francfort Dr. Jean-Emmanuel Sarry Examinateur Chargé de Recherche, INSERM, Toulouse Dr. Guillaume Bossis Examinateur Chargé de Recherche, CNRS, Montpellier Dr. Marc Piechaczyk Directeur de Thèse Directeur de Recherche, CNRS, Montpellier 2 Acknowledgements I dedicate this thesis to my Heavenly Father, for all the blessings he has bestowed upon me. Foremost, I would like to acknowledge the members of the jury for evaluating my work and for coming to Montpellier: Valérie Lallemand-Breitenbach and Stefan Müller as ‘rapporteurs’, and Jean-Emmanuel Sarry as ‘examinateur’. I would like to express my sincerest gratitude to Dr. Marc Piechaczyk, my thesis director, for having accepted me in his laboratory, for his strong support, and his precious discussions. Sincere thanks go to Dr. Guillaume Bossis, for his sage advice, mentoring, and for his daily support. He made my Ph.D. experience productive and stimulated me to continue in research. It has been truly a privilege for me to have Marc and Guillaume as my supervisors in a project, which I really enjoyed. I am also grateful to Dr. Jean-Emmanuel Sarry and Dr. Martin Villalba for their valuable advices and careful guidance in my annual thesis committee meeting. I also thank Dr. Jean- Emmanuel Sarry for his deep engagement, his contribution to in vivo experiments and for having accepted me in his laboratory to follow these experiments. Great thanks to the “Oncogenesis and Immunotherapy” team. I was very happy to work with each of you. Your dedication, insightful criticism and help were so precious for me. Particular thanks go to Julie and Mathias for their contribution to my project. I wish to also express my appreciation to all members of the IGMM for being part of a wonderful working environment. In my daily work I have been really blessed with friendly and kind members of the IGMM. I am also very indebted to Tamara and Claire for their sincere sharing, laughing, crying in times of difficulties and happiness. I would also like to thank Sung-Muk Choi and Young-Suk Kim for their encouragements and prayers. Many people contributed to this thesis both for its scientific aspects as well as in daily life and I express my gratitude to them. Words cannot express the feeling, love and thankfulness I have for my family who supported and encouraged me during all my studies in France and in Madagascar. Finally, thank you Stephan, for your special dedication and support during my last year of PhD. Your presence was countlessly important. ☺ Thank you to all. Without you, my thesis would not have been accomplished. ☺ 3 4 Table of Contents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EP ! ,(M)+!3Z!,*+!/1'%H)(,.%$!'(=*.$+&H!.$!/#!=+&+^./.(+!($0!'(''()/! PD ! ,(M)+!YZ!=)(//.L.=(,.%$!%L!/+$-!./%-+-,.0(/+/! 3I ! ,(M)+!DZ!/1'%H)(,.%$!.$*.M.,%&/! 3E ! 10 Preamble Acute myeloid leukemia (AML) is one of the four types of primary leukemia’s, which is characterized by large increase in the number of myeloid precursor cells. These precursors have lost their ability to differentiate and accumulate in the bone marrow. AML is a very heterogeneous disease and most subgroups are treated by chemotherapy composed of a combination of two genotoxics: one anthracycline such as daunorubicin and the nucleoside analogue Ara-C. Unfortunately, a large number of patients relapse. In spite of many efforts in the development of novel chemotherapy, no significant improvement was observed in the survival rates during the past 40 years. Nevertheless, one minor group defined as acute promyelocytic leukemia (APL), is the only one subtype, which is now cured by a differentiation therapy with very high survival rate. It has been shown recently that many cancers have impaired regulation of small-ubiquitin like modifier (SUMO) pathway and this post-translational modification might serve as a new target in the treatment of cancer. When I arrived in the lab, I first participated to an ongoing study that concerned the role of the SUMO pathway in AML response to chemotherapeutic drugs and its involvement in chemoresistance. We have shown that chemotherapeutic drugs induce a massive desumoylation of cellular proteins through the ROS-dependent inactivation of the SUMO activating and conjugating enzymes.