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Genomics of Inherited Bone Marrow Failure and Myelodysplasia Michael

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Genomics of Inherited Bone Marrow Failure and Myelodysplasia Michael Genomics of inherited bone marrow failure and myelodysplasia Michael Yu Zhang A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2015 Reading Committee: Mary-Claire King, Chair Akiko Shimamura Marshall Horwitz Program Authorized to Offer Degree: Molecular and Cellular Biology 1 ©Copyright 2015 Michael Yu Zhang 2 University of Washington ABSTRACT Genomics of inherited bone marrow failure and myelodysplasia Michael Yu Zhang Chair of the Supervisory Committee: Professor Mary-Claire King Department of Medicine (Medical Genetics) and Genome Sciences Bone marrow failure and myelodysplastic syndromes (BMF/MDS) are disorders of impaired blood cell production with increased leukemia risk. BMF/MDS may be acquired or inherited, a distinction critical for treatment selection. Currently, diagnosis of these inherited syndromes is based on clinical history, family history, and laboratory studies, which directs the ordering of genetic tests on a gene-by-gene basis. However, despite extensive clinical workup and serial genetic testing, many cases remain unexplained. We sought to define the genetic etiology and pathophysiology of unclassified bone marrow failure and myelodysplastic syndromes. First, to determine the extent to which patients remained undiagnosed due to atypical or cryptic presentations of known inherited BMF/MDS, we developed a massively-parallel, next- generation DNA sequencing assay to simultaneously screen for mutations in 85 BMF/MDS genes. Querying 71 pediatric and adult patients with unclassified BMF/MDS using this assay revealed 8 (11%) patients with constitutional, pathogenic mutations in GATA2 , RUNX1 , DKC1 , or LIG4 . All eight patients lacked classic features or laboratory findings for their syndromes. These data suggest that the current clinical practice of directed testing of individual genes failed 3 to diagnose patients with cryptic disease presentations and inform the integration of broad genetic screening into the diagnostic workup of BMF/MDS. In cases where broad screening of known genes failed to identify an inherited cause, we sought to discover new genes responsible for inherited BMF/MDS. We identified kindreds with unclassified disease presenting in multiple family members and sequenced the complete coding regions of their genomes (exome). In a family with low blood counts and malignancy, we discovered a novel germline heterozygous mutation in the transcription factor ETV6 segregating with the disease phenotype. The mutant protein is defective in transcriptional regulation, inhibits wild-type ETV6 in a dominant negative manner, and impairs hematopoiesis when expressed in human hematopoietic stem cells. Together, our studies provide new methodologies and genetic associations to enhance the diagnosis of inherited BMF/MDS. 4 5 Acknowledgements I would like to thank Akiko Shimamura for imparting upon me intellectual curiosity, critical thinking, creativity, and an unquenchable enthusiasm for science. I would like to thank Mary- Claire King for sharing with me her boundless energy, scientific rigor, and bold thinking. They always put my needs as a trainee before all else. I could not imagine mentors who are better models as scientists and human beings. I would like to thank the rest of my thesis committee, Marshall Horwitz, Stephen Tapscott, and Barry Stoddard, as well as former members Linda Wordeman and Chip Asbury, for insightful suggestions, constructive criticisms, and guidance. I would like to thank the members of the Shimamura lab, including Scott Coats, Katie Lombardo, Tomoka Nakamura, Nick Burwick, Marilyn Sanchez-Bonilla, Take Furuyama, Melisa Ruiz- Gutierrez, Aaron Seo, Phoenix Ho, and Ang Scott, for their patience in showing me the ropes and making the lab a warm and intellectually stimulating community. I would like to thank members of the King lab, Tom Walsh, Ming Lee, Suleyman Gulsuner, and Amanda Watts, for being such brilliant and hard-working collaborators. It’s been a true honor to work with them. I would like to thank all the patients and their families, for entrusting us with the most sensitive part of their being: their blueprint. They have made these studies possible and are the ultimate motivation behind all of our work. 6 I would like to thank my parents, Peng and Ning, and brother Mark for their unwavering love, encouragement, and every possible form of support. Finally, I thank my wife Solina and son Benji. Solina is the most positive, generous, resilient, and hard-working person I know. She has made this work possible, and I share it with her. Benji is my night and day; everything here is for him. 7 Table of Contents Acknowledgements .................................................................................................................... 6 Chapter 1 – Introduction ............................................................................................................10 1.1 Inherited bone marrow failure and myelodysplastic syndromes .......................................10 1.2 Traditional diagnostic paradigm of inherited BMF/MDS ...................................................10 1.3 Next-generation massively-parallel sequencing technology .............................................11 1.4 Outline of thesis ...............................................................................................................12 Chapter 2 - Genomic analysis of bone marrow failure and myelodysplastic syndromes ............14 2.1 Abstract ...........................................................................................................................15 2.2 Introduction ......................................................................................................................15 2.3 Methods ..........................................................................................................................16 2.4 Results ............................................................................................................................18 2.4.1 Validation of Gene Capture Assay ............................................................................18 2.4.2 Genetic Determination of Fanconi Anemia Subtype ..................................................19 2.4.3 Broad Genetic Screening Identifies Cryptic Presentations of Inherited BMF/MDS .....20 2.5 Discussion .......................................................................................................................23 2.6 Figures ............................................................................................................................26 2.7 Tables .............................................................................................................................29 Chapter 3 - Germline ETV6 Mutations in Familial Thrombocytopenia and Hematologic Malignancy ................................................................................................................................32 3.1 Abstract ...........................................................................................................................33 8 3.2 Introduction and Results ..................................................................................................33 3.3 Methods ..........................................................................................................................42 3.4 Discussion .......................................................................................................................39 3.5 Figures ............................................................................................................................47 3.6 Tables .............................................................................................................................55 Chapter 4 – Discussion .............................................................................................................56 4.1 Summary .........................................................................................................................56 4.2 Significance and Future Directions ..................................................................................57 Appendix A – Supplemental Materials for Chapter 2 .................................................................60 A.1 Supplementary Methods .................................................................................................60 A.2 Supplementary Figure .....................................................................................................62 A.3 Supplementary Tables ....................................................................................................63 Appendix B – Supplemental Materials for Chapter 3 .................................................................70 B.1 Supplementary Note .......................................................................................................70 B.2 Supplementary Figures ...................................................................................................75 B.3 Supplementary Tables ....................................................................................................80 Bibliography ............................................................................................................................ 129 9 Chapter 1 – Introduction 1.1 Inherited bone marrow failure and myelodysplastic syndromes Bone marrow failure (BMF) is a deficiency in blood cell production in the bone
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