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Targeting the Mitochondrial Peptidase Neurolysin in Acute Myeloid Leukemia

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Targeting the Mitochondrial Peptidase Neurolysin in Acute Myeloid Leukemia TARGETING THE MITOCHONDRIAL PEPTIDASE NEUROLYSIN IN ACUTE MYELOID LEUKEMIA By Sara Mirali A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of the Institute of Medical Science, University of Toronto © Copyright by Sara Mirali, 2020 Targeting the mitochondrial peptidase neurolysin in acute myeloid leukemia Sara Mirali Doctor of Philosophy Institute of Medical Science University of Toronto 2020 Abstract Acute myeloid leukemia (AML) cells and stem cells have unique mitochondrial characteristics with an increased reliance on oxidative phosphorylation (OXPHOS). Through a genetic screen to find novel mitochondrial targets in AML, we identified the mitochondrial peptidase, neurolysin (NLN). NLN is a metallopeptidase whose mitochondrial function is not well understood and whose role in AML has not been reported. We analyzed the expression of NLN in AML cells and normal hematopoietic cells. NLN gene expression was enhanced in 41% of AML samples and overexpression was confirmed by immunoblotting. Next, we assessed the effects of knocking down NLN in ii AML cell lines. NLN knockdown reduced AML growth by up to 70%, clonogenic growth by up to 80%, and engraftment into mouse marrow by 90%. We next identified NLN’s mitochondrial interactors by BioID-MS. NLN interacted extensively with the respiratory chain and NLN knockdown reduced OXPHOS. Moreover, NLN knockdown impaired the formation of respiratory chain supercomplexes (RCS), which promote efficient oxidative metabolism. RCS have not been previously studied in leukemia. We found that RCS assembly was increased in a subset of AML patients compared to normal hematopoietic cells and positively correlated with NLN protein expression (R2 = 0.80, p < 0.05), suggesting that NLN mediates RCS assembly in AML. Finally, we used a small molecule inhibitor of NLN (R2) in mice engrafted with primary AML and normal hematopoietic cells. Treatment with R2 reduced leukemic burden without toxicity. R2 targeted AML stem cells as evidenced by reduced engraftment in secondary experiments. In contrast, R2 did not reduce the engraftment of normal hematopoietic cells. Thus, we show that inhibition of NLN preferentially targets AML cells and stem cells. In summary, we defined a novel role of NLN in RCS formation and highlighted NLN inhibition as a potential therapeutic strategy for AML. iii Acknowledgements Throughout my academic experiences, I have been privileged to meet many inspiring and driven individuals who encouraged me to pursue science. I have learned a great deal during my time at the Schimmer lab and I am indebted to everyone who has helped me on this journey. I extend my sincerest gratitude to my supervisor, Dr. Aaron D. Schimmer. Aaron is truly dedicated to his students. His patience and support gave me the space to grow as a scientist and I am grateful for his advice and mentorship over the years. I could not have asked for a more kind and understanding supervisor. I thank my colleagues in the Schimmer lab who made my time in the lab both enjoyable and memorable. In particular, I thank Rose Hurren, who approached every experiment with dedication and enthusiasm. I also thank Marcela Gronda for her technical and scientific support. Rose and Marcela helped me greatly throughout graduate school with their expertise. I am grateful for their friendship and I will miss our daily discussions and laughs. I’d like to thank my committee members, Dr. Steven M. Chan and Dr. G. Angus McQuibban, for their excellent guidance and insight over the years. I especially thank Steven, who welcomed me into his lab meetings and journal club over the past four years. Steven has been a trusted source of advice and a cherished clinician-scientist mentor. Finally, I sincerely thank my parents and my brother for their unconditional love and support throughout my academic endeavors. I especially thank my loving Mom, who I lost to cancer 4 months ago. She was, and still is, my hero, role model, and best friend. I could not have completed this project without the tireless efforts of my dad and brother, who helped me immensely through the most difficult times. iv Statement of Contributions The majority of the work was performed by Sara Mirali. Technical assistance was contributed as follows: Aaron Botham performed and analyzed the BioID-MS experiments, under the supervision of Dr. Aaron D. Schimmer. Veronique Voisin and ChangJiang Xu performed all bioinformatics analyses under the supervision of Dr. Gary D. Bader (Donnelly Centre for Cellular and Biomolecular Research, Toronto, Ontario, Canada). Rose Hurren provided technical assistance for qRT-PCR experiments, under the supervision of Dr. Aaron D. Schimmer. Neil Maclean provided technical assistance with lentiviral production for experiments involving genetic knockdowns, under the supervision of Dr. Aaron D. Schimmer. Rose Hurren and Xiaoming Wang performed and analyzed data for in vivo experiments, under the supervision of Dr. Aaron D. Schimmer. Marcela Gronda provided technical assistance for colony formation assays of primary patient samples, under the supervision of Dr. Aaron D. Schimmer. This work has been published in Science Translational Medicine (Mirali S et al. The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability. Sci Transl Med 2020;12.) v Table of Contents List of Abbreviations ................................................................................................................................. ix List of Figures ............................................................................................................................................ xi List of Tables ............................................................................................................................................ xii CHAPTER 1: INTRODUCTION .............................................................................................................. 1 1. 1. Acute Myeloid Leukemia ............................................................................................................. 1 1.1.1. Pathogenesis .......................................................................................................................... 1 1.1.2. Classification ........................................................................................................................... 4 1.1.3. Treatment ................................................................................................................................ 5 1.2. Mitochondria ................................................................................................................................... 7 1.2.1. Structure and Function .......................................................................................................... 7 1.2.2. Mitochondrial Respiratory Chain ........................................................................................ 10 1.2.3. Mitochondrial Quality Control ............................................................................................. 12 1.2.4. Mitochondrial Proteases ...................................................................................................... 15 1.3. Respiratory Chain Supercomplexes ......................................................................................... 18 1.3.1. Structure and Assembly ...................................................................................................... 18 1.3.2. LETM1 ................................................................................................................................... 20 1.3.3. Function ................................................................................................................................. 21 1.3.4. Respiratory Chain Supercomplexes in Cancer ................................................................ 23 1.4. Neurolysin ..................................................................................................................................... 24 1.4.1. Structure and Function ........................................................................................................ 24 1.4.2. Localization ........................................................................................................................... 26 1.4.3. NLN knockout mouse .......................................................................................................... 27 1.4.4. NLN inhibitors ....................................................................................................................... 28 1.5. Targeting the mitochondria in AML ........................................................................................... 28 1.5.1. Mitochondrial properties of AML cells ............................................................................... 28 1.5.2. Targeted therapies ............................................................................................................... 29 CHAPTER 2: RATIONALE AND HYPOTHESIS ................................................................................ 34 OBJECTIVES ...................................................................................................................................... 35 2.1. AIM 1: To determine the effects of NLN knockdown on the growth of leukemic cells and progenitors ..........................................................................................................................................
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