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Role of Autophagy in Normal and Malignant Hematopoiesis

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Role of Autophagy in Normal and Malignant Hematopoiesis Role of autophagy in normal and malignant hematopoiesis A dissertation submitted to the Division of Research and Advanced Studies of the University of Cincinnati in partial fulfillment of the requirement for the degree of Doctor of Philosophy (Ph.D.) in the Department and Cancer and Cell Biology of the College of Medicine 2016 by Xiaoyi Chen M.D. Sichuan University Committee Members: Maria Czyzyk-Krzeska, MD, PhD Marie-Dominique Filippi, PhD Gang Huang, PhD Daniel Starczynowski, PhD Yi Zheng, PhD (Chair) 1 Abstract In this thesis work, we investigate the role of autophagy in normal and malignant hematopoiesis. In normal hematopoiesis, we study the mechanism of autophagy regulation by mTOR in hematopoietic stem and progenitor cells (HSPCs) using genetic mTOR knockout and knock-in mouse models. We find that HSPCs have varied basal autophagy activity in different subpopulations, higher in more primitive hematopoietic stem cells (HSC) and lower in more differentiated progenitor cells, suggesting varied dependence on autophagy in these cells. We also observe that the autophagy activity responds differently to mTOR deletion in HSPCs subpopulations. HSC and GMP subpopulations show mTOR independent autophagy regulation, while CMP has increased autophagy activity upon mTOR deletion. We speculate that a compensatory kinase pathway in HSC and GMP exists to negatively regulate autophagy activity upon mTOR loss in HSC population based on our kinase inhibitor data. We also find that the autophagy response in mTOR knock-in cells is similar to mTOR knockout, suggesting that mTOR regulates autophagy through its kinase function, not a protein scaffolding effect. The autophagy response in Raptor knockout cells mimics that of the mTOR knockout, indicating that mTORC1 regulates autophagy in HSPCs. This project is progressing and more studies are needed to validate our current observations and conclusions. In malignant hematopoiesis, we investigate the therapeutic potential of inhibiting autophagy for AML treatment. We show that Kmt2a/Mll-Mllt3/Af9 AML (MA9-AML) cells have high autophagy flux compared to normal bone marrow cells, but autophagy-specific targeting, either through Rb1cc1-disruption to abolish autophagy initiation, or via Atg5-disruption to prevent autophagosome membrane elongation, does not affect the growth or survival of MA9-AML cells, either in vitro or in vivo. Mechanistically, neither Atg5 nor Rb1cc1 disruption impairs the endolysosome formation or survival signaling pathways. The autophagy inhibitor, chloroquine, i shows autophagy-independent anti-leukemic effects in vitro but has no efficacy in vivo likely due to limited achievable drug efficacy in blood. Further, vesicular exocytosis appears to mediate chloroquine resistance in AML cells and exocytotic inhibition significantly enhances the anti- leukemic effect of chloroquine. Thus, the autophagy inhibitor chloroquine can induce leukemia cell death in vitro in an autophagy-independent manner but with inadequate efficacy in vivo, and vesicular exocytosis is a possible mechanism of chloroquine resistance in MA9-AML. This study also reveals that autophagy-specific targeting is unlikely to benefit MA9-AML therapy. ii iii Acknowledgement I would like to thank my advisor, Dr. Yi Zheng, who led me into the scientific world. His talent and enthusiasm for science had inspired me throughout my Ph.D. education. He is a great mentor. The freedom that he gives to his students greatly helps us forming the ability of independent thinking, which is the most important thing I learned and valued during my graduate life. He also offered timely guidance when I got puzzled in my research. He is always patient, humorous and considerate. It has been such a great pleasure to be his student and work under his mentoring. I also want to thank other members of my thesis committee, Dr. Marie-Dominique Filippi, Dr. Maria Czyzyk-krzeska, Dr. Gang Huang, and Dr. Daniel Starczynowski for their support and thoughtful suggestions. I want to thank both the current and the previous lab members of Dr. Zheng’s laboratory. They offered me good suggestions, timely technical support and a very pleasant work environment in the past few years. I also want to thank Dr. Theodosia Kalfa for her support and encouragement. I want to thank our collaborators: Dr. Jun-Lin Guan and his lab member Song Chen, Dr. Ashish Kumar and his lab member Jason Clark, Dr. James C. Mulloy and his lab member Mark Wunderlich. iv I also want to thank the Cancer and Cell Biology Graduate program. This is a very nice program and offers students great opportunities on the way of scientific exploration. I also meet great classmates in this program and I want thank them to accompany me in these years. Lastly, my most grateful thanks go to my husband Chi for his understanding and continuous support, my daughter Jingyi for the happiness she has brought and will bring to us, and my parents for their endless love and encouragement. v Table of Contents Abstract........................................................................................................................................ i Acknowledgement ...................................................................................................................... iv Abbreviations ............................................................................................................................. ix Chapter 1 Introduction ................................................................................................................ 1 1.1. Autophagy process and regulation ...................................................................................... 2 1.1.1 Canonical autophagy process .................................................................................... 2 1.1.2 Alternative autophagy process ................................................................................... 4 1.1.3 Selective autophagy ................................................................................................... 6 1.1.4 Autophagy regulation ................................................................................................. 7 1.1.4.1 mTOR pathway .................................................................................................... 7 1.1.4.2 mTOR- independent autophagy regulation pathways .........................................10 1.1.5 Interpretation of autophagy markers ..........................................................................11 1.2. Autophagy is essential for normal hematopoiesis ...........................................................12 1.2.1 Normal hematopoiesis...............................................................................................12 1.2.2 Role of autophagy in normal hematopoiesis ..............................................................14 1.3. Autophagy is involved in hematopoietic malignancies.....................................................15 1.3.1. Hematopoietic malignancies.....................................................................................15 1.3.2. MLL rearranged acute myeloid leukemia ..................................................................17 1.3.3 Role of autophagy in leukemia ..................................................................................17 1.4 Therapeutic autophagy targeting .....................................................................................19 1.4.1 Inducing autophagy for disease treatment .................................................................19 1.4.2. Inhibiting autophagy for disease treatment ...............................................................20 1.5 Autophagy independent cancers .....................................................................................22 1.6 Significance of this thesis studies ....................................................................................23 vi 1.7 Reference ........................................................................................................................25 Chapter 2 mTOR on autophagy regulation in normal hematopoietic stem/progenitor cells (HSPCs)....................................................................................................................................40 2.1 Abstract ...........................................................................................................................41 2.2 Introduction ......................................................................................................................43 2.3 Results ............................................................................................................................46 Basal autophagy activity varies in HSPCs subpopulations .................................................46 mTOR deletion leads to the expansion of HSPCs pool ......................................................46 Response of autophagy activity to mTOR deletion varies in different HSPCs subpopulations ..........................................................................................................................................47 In HSPC subpopulations, mTOR regulates autophagy through its kinase function and through mTORC1 ...............................................................................................................47 2.4 Discussion .......................................................................................................................49 2.6 Figures ............................................................................................................................53
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