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254 A systems genomics approach to identify novel drug targets of Ewing sarcoma through ancestry-informed human iPSC modeling
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- Rachel M Moss, Kelsie Becklin, Lauren J Mills, Branden S Moriarity, Beau R Webber, Logan G Spector
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- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue s1 / April 2023
- Published online by Cambridge University Press:
- 24 April 2023, pp. 77-78
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- Article
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OBJECTIVES/GOALS: We leverage the disparate incidence of Ewing sarcoma (ES) between European (EUR) and African (AFR) ancestry to study ES tumorigenesis in iPSC-derived cells from donors with a range of AFR ancestry via functional / molecular profiling. Integrated multi-omics analysis furthers explore local regulatory networks in pursuit of novel drug targets of ES. METHODS/STUDY POPULATION: In our pilot, eight induced pluripotent stem cell lines were obtained, differentiated into neural crest cells, and then transduced with a lentivirus expressing GFP-2A-EWS/FLI1. We compared wild type (WT) to EWS-FLI1-induced cells and then compared cell survival, gene expression, and EWS-FLI1 binding differences at varying levels of EUR / AFR ancestry admixture. We will build on this pilot data by expanding the number of cell lines and measuring chromatin state. Subsequently we will refine our understanding of the relationships between local ancestry, epigenetic and gene expression changes, and phenotype in tumor progression via integration of multi-omics datasets. Our systems genomics approach will utilize directed local regulatory networks in a Bayesian structure learning framework. RESULTS/ANTICIPATED RESULTS: Induction by EWS-FLI1 resulted in gene expression changes enriched in known ES gene sets. Higher %EUR ancestry correlated with prolonged maintenance of EWS-FLI1. We identified thousands of ancestry-linked changes to gene expression and EWS-FLI1 binding. Eighty of these genes are both differentially expressed and differentially bound based on AFR ancestry admixture level and may be some of the early critical targets that initiate the cascade of molecular changes in ES. We will identify novel drug targets, with potential cross functional use of known drugs. Once we have developed directed local regulatory networks, we will use them to test in silico potential perturbations due to small molecules or novel drugs and predict expression changes. DISCUSSION/SIGNIFICANCE: With a limited number of cell lines, we identify 80 ancestry-linked candidate loci for functional validation through genome engineering. As EWS-FLI1 itself has proven elusive to direct targeting, studying its immediate downstream effects has the potential for establishing new druggable biologic pathways for treatment of ES.
3 - Epidemiology and etiology
- from Section 1 - History and general issues
- Edited by Ching-Hon Pui
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- Book:
- Childhood Leukemias
- Published online:
- 05 April 2013
- Print publication:
- 21 June 2012, pp 49-71
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Summary
Introduction
The acute leukemias of childhood are a heterogeneous group of diseases. In this review of the descriptive and analytic epidemiology of these malignancies, specific subgroups are emphasized, as defined by morphology, cytogenetic features, or molecular markers. There is evidence that specific leukemic subgroups may have distinct etiologies, and that molecular abnormalities associated with particular subgroups may be linked with specific causal mechanisms. Moreover, the mutations produced at the successive stages of leukemogenesis, from initiation through induction to promotion, may all involve separate etiologic processes.
It is also important to note that changes over time in diagnostic practice and precision may account in part for some reported epidemiologic trends. Moreover, changes in terminology and classification schemes for leukemia make it difficult to make direct comparisons between studies, particularly if risk factors differ for different subgroups. However, in assessing risk factors, studies of the childhood leukemias present several methodologic advantages. The interval between exposure to putative risk factors and onset of leukemia may be shorter, recall of exposures is likely to be better, and intervening factors may be fewer than those associated with adult leukemias. These characteristics of childhood leukemia may facilitate identification of the most likely risk factors for the various leukemic subgroups. Furthermore, they lend themselves to an approach that includes both population studies and molecular epidemiologic techniques, permitting the design of research to assess genetic–environmental causal interactions. As studies of potential environmental causes of childhood leukemia have now accumulated to a degree that allows data synthesis, and in order to succinctly summarize the literature, recent meta-analyses rather than individual studies are cited preferentially below.
3 - Epidemiology and etiology
- from Part I - History and general issues
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- By Logan G. Spector, Assistant Professor, Division of Pediatric Epidemiology & Clinical Research, Julie A. Ross, Professor, Division of Pediatric Epidemiology & Clinical Research, Leslie L. Robison, Professor, Division of Pediatric Epidemiology & Clinical Research, Smita Bhatia, Director Epidemiology and Outcomes Research, Division of Pediatrics, City of Hope National Medical Center, Duarte, CA, USA
- Edited by Ching-Hon Pui
-
- Book:
- Childhood Leukemias
- Published online:
- 01 July 2010
- Print publication:
- 02 February 2006, pp 48-66
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- Chapter
- Export citation
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Summary
Introduction
The acute leukemias of childhood are a heterogeneous group of diseases. In reviewing the descriptive and analytic epidemiology of these malignancies, we have emphasized specific subgroups, as defined by morphology [the French-American-British (FAB) classification], cytogenetic features, or molecular markers. There is evidence that specific subtypes of leukemia may have distinct etiologies, and that molecular abnormalities associated with particular subtypes may be linked with specific causal mechanisms. Moreover, the mutations produced at the successive stages of leukemogenesis, from initiation through induction to promotion, may all involve separate etiologic processes.
It is also important to note that changes over time in diagnostic practice and precision may account in part for some reported epidemiologic trends. Moreover, changes in terminology and classification schemes for leukemia make it difficult to perform direct comparisons among studies, especially if risk factors differ for different subgroups. However, in assessing risk factors, studies of the childhood leukemias present several methodologic advantages. The interval between exposure to putative risk factors and the onset of leukemia may be shorter, recall of exposures is likely to be better, and intervening factors may be fewer than those associated with adult leukemias. These characteristics of childhood leukemia may facilitate identification of the most likely risk factors for each leukemia subtype. Furthermore, they lend themselves to an approach that includes both population studies and molecular epidemiologic techniques, permitting the design of research to assess genetic-environmental causal interactions.