RESUMO
Among mutations in human Runx1/AML1 transcription factors, the t(8;21)(q22;q22) genomic translocation that creates an AML1-ETO fusion protein is implicated in etiology of the acute myeloid leukemia. To identify genes and components associated with this oncogene we used Drosophila as a genetic model. Expression of AML1-ETO caused an expansion of hematopoietic precursors in Drosophila, which expressed high levels of reactive oxygen species (ROS). Mutations in functional domains of the fusion protein suppress the proliferative phenotype. In a genetic screen, we found that inactivation of EcRB1 or activation of Foxo and superoxide dismutase-2 (SOD2) suppress the AML1-ETO-induced phenotype by reducing ROS expression in the precursor cells. Our studies indicate that ROS is a signaling factor promoting maintenance of normal as well as the aberrant myeloid precursors and suggests the importance of antioxidant enzymes and their regulators as targets for further study in the context of leukemia.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Drosophila/genética , Expressão Gênica , Sistema Hematopoético/metabolismo , Hemócitos/citologia , Proteínas de Fusão Oncogênica/genética , Proteínas de Fusão Oncogênica/metabolismo , Animais , Proliferação de Células , Subunidade beta de Fator de Ligação ao Core/metabolismo , DNA/metabolismo , Drosophila/metabolismo , Proteínas de Drosophila/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Sistema Hematopoético/citologia , Hemócitos/metabolismo , Humanos , Larva/citologia , Larva/metabolismo , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Fenótipo , Proteína 1 Parceira de Translocação de RUNX1 , Espécies Reativas de Oxigênio/metabolismo , Receptores de Esteroides/metabolismo , Superóxido Dismutase/metabolismoRESUMO
Using a large consortium of undergraduate students in an organized program at the University of California, Los Angeles (UCLA), we have undertaken a functional genomic screen in the Drosophila eye. In addition to the educational value of discovery-based learning, this article presents the first comprehensive genomewide analysis of essential genes involved in eye development. The data reveal the surprising result that the X chromosome has almost twice the frequency of essential genes involved in eye development as that found on the autosomes.