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Universidade Nova De Lisboa the Role of Complex Chromosome Universidade Nova de Lisboa Faculdade de Ciências Médicas The Role of Complex Chromosome Translocations in Leukemia Luís Miguel Ramos Vieira Doutoramento em Ciências da Vida Especialidade de Biologia Molecular e Celular 2011 i The Role of Complex Chromosome Translocations in Leukemia ii iii Universidade Nova de Lisboa Faculdade de Ciências Médicas The Role of Complex Chromosome Translocations in Leukemia Luís Miguel Ramos Vieira Licenciado em Biologia pela Faculdade de Ciências da Universidade de Lisboa Dissertação Apresentada para Obtenção do Grau de Doutor em Ciências da Vida Especialidade de Biologia Molecular e Celular Professora Orientadora: Doutora Maria Gomes da Silva 2011 iv v Para os meus pais vi vii In this dissertation parts of text were transcribed from the following publications and manuscript: 1. Vieira L, Marques B, Cavaleiro C, Ambrósio AP, Jorge M, Neto A, Costa JM, Júnior EC, Boavida MG (2005) Molecular cytogenetic characterization of rearrangements involving 12p in leukemia. Cancer Genet Cytogenet 157 : 134-139. My contribution to this publication included selection of cosmid, bacterial artificial chromosome (BAC) and yeast artificial chromosome (YAC) clones, growth of clone colonies, preparation of DNA and labeling of clones for fluorescence in situ hybridization (FISH) analysis. I also performed reverse transcription-polymerase chain reaction (RT-PCR) studies and sequencing analysis of ETV6 -RUNX1 fusion transcripts. 2. Vieira L, Sousa AC, Matos P, Marques B, Alaiz H, Ribeiro MJ, Braga P, da Silva MG, Jordan P (2006) Three-way translocation involves MLL, MLLT3 and a novel cell cycle control gene, FLJ10374 , in the pathogenesis of acute myeloid leukemia with t(9;11;19)(p22;q23;p13.3). Genes Chromosomes Cancer 45 : 455-469. I have contributed to this publication through the identification of the CCDC94 -MLL genomic fusion by long distance inverse-polymerase chain reaction (LDI-PCR), detection of truncated CCDC94 transcripts by 3´ rapid amplification of cDNA ends (RACE), analysis of CCDC94 expression in leukemic cell lines and normal human tissues by RT-PCR, amplification and cloning of full-length CCDC94 cDNA in expression vectors, evaluation of CCDC94 suppression by RT-PCR in short interfering RNA (siRNA)- treated cells and computational sequence analysis, including design of primers and siRNA oligos, selection of restriction enzymes for LDI-PCR experiments, analysis of DNA, RNA and protein sequences, as well as selection of MLLT3 and CCDC94 clones for use as FISH probes. 3. Vieira L, Vaz A, Ambrósio AP, Nogueira M, Marques B, Silva E, Matos P, Pereira AM, Jordan P, da Silva MG. Three-way translocation (X;20;16)(p11;q13;q23) in essential thrombocythemia implicates NFATC2 in disregulation of GM-CSF expression and megakaryocyte proliferation (submitted). My contribution to this manuscript included delimitation of a chromosome 20q deletion by polymerase chain reaction (PCR) analysis of short tandem repeat polymorphisms, preparation of genomic DNA for whole-genome array study, analysis of array data, 5´ RACE analysis of NFATC2 transcripts, 3´ RACE analysis of WWOX transcripts, analysis of NFATC2 expression in normal human tissues by RT-PCR, detection of a transcribed single nucleotide polymorphism in NFATC2 by PCR, RT-PCR and sequencing analysis, mutational analysis of JAK2 and NFATC2 , evaluation of NFATC2 suppression in siRNA-treated cells by real-time quantitative PCR (Q-PCR), analysis of NFATC2 expression in patients and controls by Q-PCR, analysis of Q-PCR data in cell lines and human samples, and computational sequence analysis including design of primers and siRNA oligo, selection of YAC, BAC and P1-derived artificial chromosome (PAC) clones for FISH studies, as well as analysis of DNA, RNA and protein sequences. I also wrote the manuscripts and prepared all figures and tables. viii ix Acknowledgments I wish to acknowledge primarily Prof. Maria Gomes da Silva for accepting to be my thesis supervisor. Prof. M. Gomes da Silva provided the best moments in my career by believing in this project from the first minute and allowing it to become a reality. I also wish to acknowledge for her excellent discussions of experimental results and scientific contributions to this thesis, as well as for continuous motivation and sincere friendship for the last 6 years. I also wish to acknowledge all the researchers and clinicians who were co-authors of the publications included in this dissertation. Above all, I am sincerely indebted to Prof. Maria Guida Boavida for accepting me as her student at the Departamento de Genética (INSA) in October 1993 and for an inestimable teaching of the world of cancer genetics. I am also deeply grateful to Dr. Paula Ambrósio for priceless karyotype studies and to Dr. Bárbara Marques for notable FISH experiments. In addition, I am also trully grateful to Prof. Peter Jordan for providing outstanding scientific support. Finally, I wish to sincerely thank Elizabeth Silva for performing most of the molecular diagnostics of leukemia while I was committed to research work. At the institutional level I must thank Instituto Nacional de Saúde Dr. Ricardo Jorge for providing all the necessary laboratory facilities that made this thesis possible. This would not also been achieved without relevant financial support from Liga Portuguesa Contra o Cancro, Fundação para a Ciência e a Tecnologia and Associação Portuguesa Contra a Leucemia. My final acknowledgment is addressed to my wife Célia, to whom I am grateful for unrestricted love, companionship and endless support throughout the last 14 years. x xi Preface My interest in genetics began when I was a Biology student at Faculdade de Ciências da Universidade de Lisboa in the early 90´s. During the last 2 years of my graduation I worked as a volunteer at the Departamento de Biologia Vegetal in the genetics of microorganisms. When I graduated in 1993 my genetics teacher Prof. Graça Fialho recommended that I should pursue my professional interests in genetics at the Departamento de Genética of the Instituto Nacional de Saúde Dr. Ricardo Jorge (DG-INSA). At that time, Prof. Maria Guida Boavida, who was in charge of DG-INSA, was looking for a graduate student to initiate the molecular diagnosis of leukemias in the laboratory. Luckily, I was accepted for that assignment and together with my colleagues Paula Ambrósio and Bárbara Marques we constituted a small team developing conventional cytogenetics, fluorescence in situ hybridization and molecular techniques to interpret and report chromosomal abnormalities in leukemia patients. With time, however, I gradually become interested in pursuing a more research directed activity towards the characterization of novel chromosomal abnormalities in leukemia. I started this endeavour with a comprehensive retrospective analysis of leukemia karyotype registries at the DG-INSA and Laboratório de Hematologia of the Instituto Português de Oncologia de Francisco Gentil (LH-IPOFG) in Lisbon, under the guidance of Prof. Maria Guida Boavida and Prof. Maria Gomes da Silva, respectively. The purpose was to select samples carrying reciprocal chromosome translocations undescribed in the literature and potentially use them to pursue molecular investigation of novel breakpoint locations and associated fusion genes. After a first scrutiny, I subsequently focused my interest in translocations in which one of the breakpoint locations was already known to constitute a recurrent target site. Moreover, only cytogenetic records which were obtained at the time of initial diagnosis were considered. Both approaches increased the likelihood of identifying novel leukemogenic fusion genes. The final output of the review comprised a total of 5 different translocations, including 2 collected from DG-INSA database and 3 obtained from the LH- IPOFG database. Incidently, preliminary studies disclosed that at least one additional chromosome was involved in 4 out of the 5 selected translocations, thus revealing an unexpected complex nature. A fundamental question then rose to my mind: Is the role of extra breakpoint locations involved in complex translocations merely accessory or is it also relevant to the proliferation and survival of the leukemic clone? I then addressed Prof. Maria Gomes da Silva in 2005 with a tentative idea for a PhD project under her supervision involving the role of complex xii chromosome translocations in leukemogenesis. This project soon became a reality and 6 years later all I can say is that I have made the right choice. xiii Abstract Tumourigenesis is a multistep process which results from the accumulation of successive genetic mutations in a normal cell. In leukemia for instance, recurrent translocations play a part in this process by generating fusion genes which lead to the production of hybrid proteins with an oncogenic role. However, a minor subset of chromosomal translocations referred to as complex or variant involves extra breakpoints at variable genome locations in addition to those implicated in the formation of fusion genes. We aimed to describe in this work the role, if any, of genes located at extra breakpoint locations or which are affected by breakpoint-adjacent deletions through the study of 5 leukemia patients. Two of the patients presented with ETV6 (12p13)-RUNX1 (21q22) and MLL (11q23)- MLLT3 (9p22) fusion genes as a result of a t(12;21;5) and a t(9;11;19), respectively. Detailed molecular characterization of the extra breakpoint at chromosome 19 in the latter case revealed that a novel ubiquitously
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