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Novel Mechanisms of Transcriptional Regulation by Leukemia Fusion Proteins

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Novel Mechanisms of Transcriptional Regulation by Leukemia Fusion Proteins Novel mechanisms of transcriptional regulation by leukemia fusion proteins A dissertation submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the Department of Cancer and Cell Biology of the College of Medicine by Chien-Hung Gow M.S. Columbia University, New York M.D. Our Lady of Fatima University B.S. National Yang Ming University Dissertation Committee: Jinsong Zhang, Ph.D. Robert Brackenbury, Ph.D. Sohaib Khan, Ph.D. (Chair) Peter Stambrook, Ph.D. Song-Tao Liu, Ph.D. ABSTRACT Transcription factors and chromatin structure are master regulators of homeostasis during hematopoiesis. Regulatory genes for each stage of hematopoiesis are activated or silenced in a precise, finely tuned manner. Many leukemia fusion proteins are produced by chromosomal translocations that interrupt important transcription factors and disrupt these regulatory processes. Leukemia fusion proteins E2A-Pbx1 and AML1-ETO involve normal function transcription factor E2A, resulting in two distinct types of leukemia: E2A-Pbx1 t(1;19) acute lymphoblastic leukemia (ALL) and AML1-ETO t(8;21) acute myeloid leukemia (AML). E2A, a member of the E-protein family of transcription factors, is a key regulator in hematopoiesis that recruits coactivators or corepressors in a mutually exclusive fashion to regulate its direct target genes. In t(1;19) ALL, the E2A portion of E2A-Pbx1 mediates a robust transcriptional activation; however, the transcriptional activity of wild-type E2A is silenced by high levels of corepressors, such as the AML1-ETO fusion protein in t(8;21) AML and ETO-2 in hematopoietic cells. It is unclear how this context-dependent regulation of E2A-dependent transcription allows E2A protein to regulate transcription in response to variable intracellular levels of corepressor. In this study, we discovered that unlike HEB, another E-protein, the activation domain 1 (AD1) of E2A is inhibited for corepressor interaction by E2A-specific amino acid changes in the p300/CBP and ETO target motif, which interacts with only one of these targets at a time. At physiological levels of corepressor, E2A-Pbx1 escapes endogenous ETO-2 binding to confer its oncogenic ability via AD1 and AD2 cooperative activity to facilitate coactivator recruitment. In the presence of aberrantly i high levels of AML1-ETO, E2A interacts with the corepressor to silence expression of E-protein target genes. This process requires the downstream ETO-interacting sequence (DES) domain of E2A to compensate for the weak binding between E2A-AD1 and AML1-ETO. This novel E2A-specific cofactor exchange mechanism provides an explanation for the specific E2A determinants that oppositely link corepressor function to distinct leukemogenic pathways. In the second part of this study, we explored the regulatory mechanism of histone deacetylase 3 (HDAC3), which mediates chromatin structural dynamics to control transcription. In E-protein-mediated transcription, corepressor AML1-ETO/ETO associates with HDAC3 by recruiting nuclear receptor corepressors N-CoR/SMRT to packed chromatin, thus repressing transcription. Functional HDAC3 must form a stable complex with N-CoR or SMRT, which individually and independently bind to HDAC3. We identified a novel cell-independent HDAC3 regulatory mechanism, which is significant for its reduced protein levels of corepressor (N-CoR or SMRT) and accelerates HDAC3 clearance to prevent complex formation between HDAC3 and its other corepressor. We also demonstrated the formation of an HDAC3-corepressor complex via a stepwise procedure in which the unique C-terminus of HDAC3 is critical for the assembly process. These findings may be useful in efforts to reverse the leukemogenic phenotypes and in the development of new treatments for leukemia. ii iii PREFACE The work presented in this dissertation was primarily designed by my advisor Dr. Jinsong Zhang. I helped and contributed to the overall design and undertook the majority of the work presented in Chapter 2. I served as the first author of the paper corresponding to the work presented in Chapter 2. Other authors of the paper have also contributed to the work reported therein. The work presented in Chapter 3 is primarily done by Chun Guo. I contributed to some experiments reported in the paper. iv ACKNOWLEDGMENTS I would like to thank all of those individuals who offered their support and assistance during my graduate career. I am indebted to my mentor, Dr. Jinsong Zhang, for giving me the opportunity to perform my research in his lab and for his continuous support during the past three years of my graduate studies. Dr. Zhang is very enthusiastic about research, and I have learned a great deal from him. Under Dr. Zhang’s guidance, I have learned to equip myself with modern skills in molecular biology and basic concepts in biochemistry, thereby achieving maturity as a scientist. My sincere gratitude goes out to the members of my thesis committee, Drs. Robert Brackenbury, Sohaib Khan, Peter Stambrook, and Song-Tao Liu, for their insightful advice and important questions that guided my inquiry. I also thank the Cancer and Cell Biology Graduate Program for offering me exceptional graduate training. It is also my great pleasure to acknowledge the former and current members of Dr. Zhang’s lab for their technical support. I especially thank Mrs. Chun Guo for her valuable insight on the experimental details and data interpretation. I thank the former and current program secretaries for answering all of my questions related to graduate studies. I am also indebted to all of the students and faculty members in the program for their support. I am grateful to my family for their support throughout my graduate career. My parents and parents-in-law consistently showered me with encouragement, love, and care. Finally, v I wish to express my deepest gratitude to my beloved wife, Wan-Jung Hsu, and my daughter, Jen-Yuan Gow, who have been the best companions; they have made graduate school life much more pleasant. vi TABLE OF CONTENTS ABSTRACT .......................................................................................................................i PREFACE.........................................................................................................................iv ACKNOWLEDGMENTS.............................................................................................v TABLE OF CONTENTS ...............................................................................................vii LIST OF FIGURES .......................................................................................................xi LISTOF TABLES...........................................................................................................xv LIST OF ABBREVIATIOS ………………………………..……………………….xvi CHAPTER 1. General Introduction and Background Review…………….…….1 PART I. General concepts of transcriptional regulation in eukaryotes.………….….1 A. Transcription factor and transcriptional regulation…………………………1 B. Chromatin structure ……..………………...………………….….…..…….4 C. Transcriptional activators and coactivators ……….…………..….…..5 D. Transcriptional repressors and corepressors ……………..………...…6 E. Acute leukemia is related to transcriptional deregulation...................9 E.1. Acute lymphocytic leukemia (ALL)………..…….……………......10 E.2. Acute myeloid leukemia (AML)….……………....….……………..11 PART II. Connecting two types of acute leukemia to E-proteins…………...……….12 A. E-proteins are transcription factors that bind to DNA E-box sites …….12 B. Roles of E-proteins in hematopoiesis ……………………………...……..14 C. E-proteins are involved in different types of acute leukemia……….…….15 C.1. E2A-Pbx1 and E2A-HLF: Chromosomal translocations involving the E2A gene in acute lymphoblastic leukemia…………...........15 C.2. Transcriptional activity of E-proteins is silenced by AML1-ETO in AML……………………………………..………….16 C.2.1. Transcription factor AML1……………………..………………16 C.2.2. AML1-ETO and E-proteins ……………………………………17 vii PART III. Regulation of E-protein–mediated transcription in acute leukemia..18 A. Context-dependent regulation of E2A-dependent transcription ………...18 A.1. E2A-Pbx1 alters the transcriptional regulation of PBX1/HOX/MEIS target genes …………………...…………………..…………………18 A.1.1. Both PBX1 and HOX transcription factors are crucial in hematopoiesis……………………………………………….18 A.1.2. E2A-Pbx1 fusion proteins replace original PBX1 binding sites………………...………………………………………….19 A.2. The E2A portion of the E2A-Pbx1 fusion mediates robust transcriptional activation through the coactivator–E2A interaction…20 A.2.1. p300/CBP interacts with many transcription factors that have significant roles in hematopoiesis…………………...….…..20 A.2.2. p300 /CBP and GCN5 contribute to a robust transcriptional activation in E2A-Pbx1–induced leukemia................................21 A.2.2.1.p300/CBP and the LXXLL motif…………………………..22 A.2.2.2.GCN5 and the LDFS motif………..…...…..……..…………23 B. The transcriptional activity of wild-type E-proteins is silenced by high levels of corepressors………………………..………….……………24 B.1. ETO forms stable complexes with E-proteins through multivalent binding…………..……………………………………24 B.2. The PCET motif in the AD1 domain of E-proteins ……………… 25 B.3. The DES domain of E-proteins is involved in transcription activation and repression…………………….…………………………….….27 B.4. The AD2 domain of E-proteins activates transcription either independently or in cooperation with AD1…..……………………..28 B.5. AML1-ETO oligomerization requires
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