University of Texas at El Paso DigitalCommons@UTEP Open Access Theses & Dissertations 2014-01-01 Functional Genomic and Proteomic Analysis of Highly Drug Resistant Chronic Myeloid Leukemia Derrick Matthew aO xaca University of Texas at El Paso, [email protected] Follow this and additional works at: https://digitalcommons.utep.edu/open_etd Part of the Cell Biology Commons, and the Oncology Commons Recommended Citation Oaxaca, Derrick Matthew, "Functional Genomic and Proteomic Analysis of Highly Drug Resistant Chronic Myeloid Leukemia" (2014). Open Access Theses & Dissertations. 1310. https://digitalcommons.utep.edu/open_etd/1310 This is brought to you for free and open access by DigitalCommons@UTEP. It has been accepted for inclusion in Open Access Theses & Dissertations by an authorized administrator of DigitalCommons@UTEP. For more information, please contact [email protected]. FUNCTIONAL GENOMIC AND PROTEOMIC ANALYSIS OF HIGHLY DRUG RESISTANT CHRONIC MYELOID LEUKEMIA DERRICK MATTHEW OAXACA Department of Biological Sciences APPROVED: Robert A. Kirken, Ph.D., Chair Marc B. Cox, Ph.D. Ming-Ying Leung, Ph.D. Charles Ambler, Ph.D. Dean of the Graduate School Copy Right © By Derrick Oaxaca 2014 Dedication Page I dedicate this thesis to three important people in my life. The first two being both my parents David and Yvette Oaxaca, for their endless love and support. They have provided me lifelong lessons of how we must work hard for everything we want in life. I also dedicate this thesis to my best friend, and girlfriend, Sarah Chenausky who always displayed patience, enduring love, and belief in me like no other. FUNCTIONAL GENOMIC AND PROTEOMIC ANALYSIS OF HIGHLY DRUG RESISTANT CHRONIC MYELOID LEUKEMIA By DERRICK MATTHEW OAXACA, Bachelors of Science THESIS Presented to the Faculty of the Graduate School of The University of Texas at El Paso in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE Department of Biological Sciences THE UNIVERSITY OF TEXAS AT EL PASO August 2014 Acknowledgments The work performed within this thesis could not have been accomplished if it were not for the help and knowledge of many people, in particular my lab mates. I would like to thank my fellow graduate students, friends, and lab mates Steven Martinez, Blanca Ruiz, Elisa Robles, and Stephanie Moreno for all the times they helped me complete a project or cheered me up when an experiment did not go well. I would like to specifically thank Dr. Georgialina Rodriguez for all the times that she explained to me the rationale underlying a particular experiment and her willingness to always answer any question that I had. A significant portion of this work would not have been possible if it were not for the expertise and mentoring provided by Dr. Jeremy Ross. Inside the lab he taught me almost everything I know and I truly appreciate all his time and efforts he spent instructing me. I would like to emphasize how grateful and appreciative I am for Dr. Robert Kirken taking me in as an undergraduate student, which eventually led to my enrollment as a graduate student. Dr. Kirken has been an inspirational and exemplary mentor to me. I appreciate Dr. Kirken’s methods in always challenging his students to seek out investigation and explanation of a given project. I cannot express the gratitude I have towards Dr. Kirken’s support over the years. Finally, I would like to specially thank Sun ah Yang-Reid for all the times she assisted me with many experiments that allowed me to complete my objectives. v Table of Contents Signature Page ................................................................................................................................. i Copy Right ...................................................................................................................................... ii Dedication Page ............................................................................................................................. iii Title Page ....................................................................................................................................... iv Acknowledgments........................................................................................................................... v Table of Contents ........................................................................................................................... vi List of Figures .............................................................................................................................. viii List of Tables ................................................................................................................................. ix Abstract ........................................................................................................................................... x Chapter I: General Introduction ...................................................................................................... 1 1.1 Cancer and Society ................................................................................................................... 2 1.2 Cancer and Cell Signaling ........................................................................................................ 3 1.3 Hematologic Malignancies ....................................................................................................... 6 1.4 The Immune System ................................................................................................................. 8 1.5 Chronic Myeloid Leukemia .................................................................................................... 10 Chapter II: Signaling Networks within Myeloid Cells ................................................................. 18 2.1 JAK-STAT Pathway ............................................................................................................... 19 2.2 Src Family Kinases (SFKs) ..................................................................................................... 22 2.3 Ras Signaling .......................................................................................................................... 25 2.4 Raf/MEK/ERK Pathway ......................................................................................................... 27 2.5 P38 MAPK and JNK/SAPK ................................................................................................... 29 2.6 PI3K Signaling ........................................................................................................................ 31 2.7 TGFβ/SMAD Pathway ........................................................................................................... 33 2.8 Protein Kinase C (PKC) .......................................................................................................... 35 2.9 Hypothesis and Significance ................................................................................................... 38 Chapter III: Activated Pathways that are Secondary to Treatment by Small Molecule Inhibitors40 3.1 Introduction ............................................................................................................................. 41 3.2 Materials and Methods ............................................................................................................ 44 3.3 Results ..................................................................................................................................... 47 3.4 Discussion ............................................................................................................................... 55 Chapter IV: Identification of Small Molecule Inhibitors that Selectively Induce Cell Death in Imatinib Resistant Chronic Myeloid Leukemia ............................................................................ 58 4.1 Introduction ............................................................................................................................. 59 4.2 Materials and Methods ............................................................................................................ 59 4.3 Results ..................................................................................................................................... 60 4.4 Discussion ............................................................................................................................... 67 Chapter V: Genetic Alterations in Drug Resistant Chronic Myeloid Leukemia .......................... 71 5.1 Introduction ............................................................................................................................. 72 5.2 Materials and Methods ............................................................................................................ 73 vi 5.3 Results ..................................................................................................................................... 77 5.4 Discussion: .............................................................................................................................. 86 Chapter VI: Overview ................................................................................................................... 88 Literature Cited ............................................................................................................................. 92 Appendix ....................................................................................................................................