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TSLP-Induced Mechanisms and Potential Therapies for CRLF2 B-Cell Acute Lymphoblastic Leukemia Olivia L

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TSLP-Induced Mechanisms and Potential Therapies for CRLF2 B-Cell Acute Lymphoblastic Leukemia Olivia L Loma Linda University TheScholarsRepository@LLU: Digital Archive of Research, Scholarship & Creative Works Loma Linda University Electronic Theses, Dissertations & Projects 6-2015 TSLP-induced Mechanisms and Potential Therapies for CRLF2 B-cell Acute Lymphoblastic Leukemia Olivia L. Francis Follow this and additional works at: http://scholarsrepository.llu.edu/etd Part of the Anatomy Commons, Genetic Phenomena Commons, Hemic and Lymphatic Diseases Commons, and the Medical Anatomy Commons Recommended Citation Francis, Olivia L., "TSLP-induced Mechanisms and Potential Therapies for CRLF2 B-cell Acute Lymphoblastic Leukemia" (2015). Loma Linda University Electronic Theses, Dissertations & Projects. 282. http://scholarsrepository.llu.edu/etd/282 This Dissertation is brought to you for free and open access by TheScholarsRepository@LLU: Digital Archive of Research, Scholarship & Creative Works. It has been accepted for inclusion in Loma Linda University Electronic Theses, Dissertations & Projects by an authorized administrator of TheScholarsRepository@LLU: Digital Archive of Research, Scholarship & Creative Works. For more information, please contact [email protected]. LOMA LINDA UNIVERSITY School of Medicine in conjunction with the Faculty of Graduate Studies ____________________ TSLP-induced Mechanisms and Potential Therapies for CRLF2 B-cell Acute Lymphoblastic Leukemia by Olivia L Francis ____________________ A Dissertation submitted in partial satisfaction of the requirements for the degree Doctor of Philosophy in Anatomy ____________________ June 2015 © 2015 Olivia L Francis All Rights Reserved Each person whose signature appears below certifies that this dissertation in his/her opinion is adequate, in scope and quality, as a dissertation for the degree Doctor of Philosophy. , Chairperson Kimberly Payne, Associate Professor of Pathology & Human Anatomy Sinisa Dovat, Associate Professor of Pediatrics, Pennsylvania State University, Hershey Mary Kearns-Jonker, Associate Professor of Pathology & Human Anatomy Kerby Oberg, Professor of Pathology & Human Anatomy Ubaldo Soto-Wegner, Assistant Research Professor of Microbiology David J. Weldon, Associate Professor of Pharmaceutical Science, School of Pharmacy iii ACKNOWLEDGEMENTS All glory and honor be given to God for the magnificent work he has done. He has filled me with wisdom and has revealed the secret nuances of science from the inception to the completion of this project. I express sincere gratitude to Dr. Payne who willingly gave me the opportunity to explore and fulfill my dream of contributing to the diagnosis and treatment of children with Leukemia. Her support, passion, creativity and dedication to making a positive difference in the world and her overall contributions to the university in relation to pediatric cancer speaks volumes of her dedication to this cause. I extend special thanks to my committee members for scientific guidance and constructive criticisms that allowed this project to make indelible contributions to the scientific community. To my lab colleagues, with whom I have laughed, vented, enjoyed great conversations and great meals, I say thank you. I could not complete this journey without all of you. Finally, to my family and friends words cannot express the value of your support and prayers for me over the years. God called each of you specifically to fulfill that purpose and he will bless all of you abundantly in return for the kindness you have shown me. I am forever indebted to all of you and so I say thank you. iv CONTENTS Approval Page .................................................................................................................... iii Acknowledgements ............................................................................................................ iv Table of Contents .................................................................................................................v List of Tables .......................................................................................................................x List of Figures .................................................................................................................... xi List of Abbreviations ....................................................................................................... xiii Abstract ............................................................................................................................ xvi Chapter 1. Introduction ..............................................................................................................1 Normal B-cell Development ..............................................................................1 Stages of Early B-cell Differentiation .........................................................1 Cytokine Function in Normal B-cells ..........................................................2 TSLP and IL-7 Signaling in Normal B-cells ...............................................3 The Role of Transcription Factors in Normal B-cells .................................4 High-risk B-cell Acute Lymphoblastic Leukemia .............................................5 Significance of Studies .....................................................................................7 Identifying Molecular Targets in CRLF2 Signaling Pathway .....................7 Reducing Childhood Cancer Health Disparities ..........................................8 Identifying Therapies to Target CRLF2 Signaling Pathway .......................9 Scientific Approach of Studies ..........................................................................9 Rationale ......................................................................................................9 Innovation ..................................................................................................12 A Novel In-vivo Model to Identify TSLP-induced Molecular Mediators in CRLF2 B-ALL ...............................................................12 New Therapeutics to Target the CRLF2 Signaling Pathway .............13 Tools and Models ......................................................................................13 v CRLF2 B-ALL Cell Lines ...................................................................13 Primary CRLF2 B-ALL Cells ..............................................................14 HTSLP+/HTSLP- Xenograft Samples .................................................14 References ........................................................................................................15 2. A Novel Xenograft Model to Study the Role of TSLP-CRLF2 Signals in Normal and Malignant Human B-Lymphopoiesis .................................................20 Abstract ............................................................................................................20 Abbreviations ...................................................................................................22 Introduction ......................................................................................................23 Materials and Methods .....................................................................................25 Human Samples and Cell Lines .................................................................25 Mice ..........................................................................................................25 Flow Cytometry .........................................................................................25 Stromal Cell Transduction .........................................................................26 Xenograft Transplantation .........................................................................26 Microarray Analysis of Gene Expression in CRLF2 B-ALL Cells ...........26 Results ..............................................................................................................27 Mouse TSLP Does not Activate the Human TSLP Receptor Complex .....................................................................................................27 Engineering Xenograft Mice to Express Normal Serum Levels of Human TSLP .............................................................................................30 Human TSLP Produced in Xenograft Mice Shows Functional Effects on Normal Human B- lineage Cells ..............................................34 Human TSLP in Xenograft Mice Induces MTOR-regulated Genes in Primary CRLF2 B-ALL Cells................................................................36 TSLP Responsiveness is Reduced in Primary CRLF2 B-ALL Cells Expanded in Xenografts without HTSLP ..................................................40 Discussion ........................................................................................................43 References ........................................................................................................47 3. TSLP Exerts Effects that are Distinct from IL-7 During Normal Human B- cell Development ...................................................................................................51 Abstract ............................................................................................................51 Abbreviations ...................................................................................................53 Introduction ......................................................................................................54 Materials and Methods .....................................................................................55
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