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Pan-Cancer Study of INPP4B Reveals Its Unexpected Oncogene-Like Role and Prognostic Significance

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Pan-Cancer Study of INPP4B Reveals Its Unexpected Oncogene-Like Role and Prognostic Significance Pan-Cancer Study of INPP4B Reveals its Unexpected Oncogene-Like Role and Prognostic Significance By Irakli Dzneladze A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Medical Biophysics University of Toronto © Copyright by Irakli Dzneladze, 2017 Pan-Cancer Study of INPP4B Reveals its Unexpected Oncogene-Like Role and Prognostic Significance Irakli Dzneladze Doctor of Philosophy Department of Medical Biophysics, University of Toronto, 2017 ABSTRACT The work presented in this thesis demonstrates and explores the unexpected oncogenic role of a previously known tumor suppressor inositol polyphosphate-4-phosphatase, type-II (INPP4B). Specifically, INPP4Bhigh AML was found to be associated with poor response to therapy, and shorter overall- and event-free survival. Multivariate analysis revealed that INPP4B expression status improves one’s ability to predict patient outcome when added to current prognostic models. Furthermore, INPP4Bhigh identifies a poor risk patient subgroup in the cytogenetically normal patient subpopulation. In vitro overexpression of INPP4B in AML cell lines revealed that INPP4B contributes to a more aggressive AML disease by enhancing colony forming potential, increasing proliferation, and increasing drug resistance. In addition to being the first in identifying INPP4B’s prognostic significance in AML, this thesis is amongst the first studies to uncover the unexpected oncogenic function of this previously known tumor suppressor. Next, to identify transcriptional regulators of INPP4B in AML, and characterize the pan- cancer prognostic significance of INPP4B expression status, I developed subgroup identifier (SubID), a non-median dichotomization tool for heterogeneous populations. Using SubID, I identified significant co-expression between INPP4B and the transcription factor EVI1. In vitro ii validation revealed EVI1 knockdown in EVI1high AML cell lines is associated with a significant decrease INPP4B levels. Furthermore, chromatin immunoprecipiation demonstrated EVI1 binding to the INPP4B transcription start site region. Next, in my pan-cancer analysis with SubID, I identified that INPP4B expression may be associated with patient survival in 13 different cancer types. Following stringent multiple testing and permutation corrections, I observed that INPP4Blow expression status was associated with shorter survival in kidney clear cell, liver hepatocellular, and bladder urothelial carcinomas. Conversely, INPP4Blow status was associated with longer survival in pancreatic adenocarcinoma. The unexpected oncogene-like prognostic significance of INPP4B in pancreatic adenocarcinoma was cross-validated in two additional independent pancreatic cancer datasets. Overall, the work presented in this thesis provides evidence that INPP4B expression status is associated with patient outcome in both a tumor-suppressive and oncogenic manner depending on the context. In vitro work demonstrates that overexpression of INPP4B in AML contributes to traits associated with a more aggressive disease in a causative rather than associative manner. iii ACKNOWLEDGMENTS This thesis could not have been possible without the support, hard work, and guidance of some of the most incredible people I have had the honor of meeting throughout my graduate journey. The last to be written, this was the hardest section to put together. How could I ever express my gratitude to all the people who help make one of my life’s greatest accomplishments a reality? I would to express my eternal gratitude to my supervisor, mentor, and teacher, Dr. Mark Minden. It is said that great leaders lead by example, demonstrating their own commitment to the values they inspire in others. True to this, you have always been my inspiration for hard work, dedication, passion, scientific curiosity, and perseverance. You have always been a reminder to me that true dedication is continuing to work when everyone else has gone home for the day or has thrown in the towel. I cannot thank you enough for your support and guidance when I needed it the most. It is under your guidance that I was able to develop both scientifically and personally. Thank you for always keeping your office door open to me and my ideas. I also want to thank Dr. Leonardo Salmena, whose guidance and support helped me publish my first scientific paper. Lenny, together with Dr. Minden, you helped me find the project that led to this thesis, and have supported me throughout the whole process. You helped me to navigate through my graduate journey and develop essential skills. Thank you for encouraging me to pursue my passion in bioinformatics and for all the scientific discussions. Thank you also to my supervisory committee members. Dr. Linda Penn, your expertise in experimental biology has always been invaluable in helping me optimize my protocols and design the correct experiments. Your methodical approach was also an inspiration for me to maintain my focus and complete the experiments as well and efficiently as possible. Dr. John McPherson, thank you for always helping me see the big picture. Each time we met, you encouraged me to examine what is the overall goal of my work, and what is the best way to achieve that goal. Thank you also for your technical feedback ands for helping me uncover the different facets of my work and research questions. Finally, Dr. Daniel de Carvalho, it was under yours and Dr. McPherson’s guidance that I took my very first steps in bioinformatics. Your suggestions and feedback helped me develop the fundamental skills in biostatistics, bioinformatics, and clinical data analysis. Thank you for always pointing me in the right direction. I would also like to thank Dr. Jüri Reimand, whose bioinformatic expertise and guidance helped me develop my basic idea of SubID into the tool described in this thesis. Your feedback, advice, and suggestions helped me recognize how SubID can be developed to better fulfill its function. iv I am also grateful to all the members of the Minden, Salmena, and Reimand laboratories for all your help, and for making my graduate journey an enjoyable experience. I would like to give a special thank you to Ayesha Rashid, Dr. John Woolley, and Dr. Mike Jain. Your encouragement, motivation, countless hours of discussions, feedback, and suggestions helped me finally reach the finish line. You have helped me cope with the stresses and worries that research entails. Lastly, I would like to thank my parents and dedicate this thesis to them. Mom and dad, you laid down the foundation upon which I can build my life’s accomplishments. Thank you for your love, care, and giving me the opportunities I now have. v TABLE OF CONTENTS ABSTRACT ...................................................................................................................... ii ACKNOWLEDGMENTS ............................................................................................... iv TABLE OF CONTENTS ................................................................................................ vi LIST OF TABLES ........................................................................................................... x LIST OF FIGURES ......................................................................................................... xi ABBREVIATIONS .......................................................................................................... xiv CHAPTER 1. INTRODUCTION ................................................................................... 1 1.1. INOSITOL POLYPHOSPHATE 4-PHOSPHATASE, TYPE II (INPP4B) ............ 2 1.1.1. Discovery of the 4-Phosphatase and INPP4B .......................................... 2 1.1.2. INPP4B Locus and Regulation of Expression ......................................... 5 1.1.3. INPP4B Protein and Active Site .............................................................. 7 1.2. INPP4B BIOLOGICAL ROLE ................................................................................ 9 1.2.1. INPP4B Tumor Suppressor Function ...................................................... 10 1.2.2. INPP4B Role in DNA Damage Repair, IR and Drug Resistance ............ 18 1.3. PI3K/AKT PATHWAY ........................................................................................... 20 1.3.1. Inositol Signalling and the PI3K/AKT Pathway ...................................... 22 1.3.2. INPP4B Reduces AKT Activation............................................................ 26 1.4. ACUTE MYELOID LEUKEMIA (AML) ............................................................... 27 1.4.1. Acute Myeloid Leukemia ........................................................................ 27 1.4.2. Common Genetic Abnormalities in AML ............................................... 30 1.5. THESIS RATIONALE, HYPOTHESES AND OBJECTIVES ............................... 36 vi CHAPTER 2. INPP4B OVEREXPRESSION IS ASSOCIATED WITH POOR CLINICAL OUTCOME AND THERAPY RESISTANCE IN ACUTE MYELOID LEUKEMIA ................................................................................................. 39 2.1. ABSTRACT .............................................................................................................. 40 2.2. INTRODUCTION .................................................................................................... 40 2.3. MATERIALS AND METHODS ............................................................................. 43 2.3.1. Patient Samples .......................................................................................
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