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
IntroductionRUNX genes encode highly conserved Runt domain transcription factors (AML/RUNX proteins), which play critical roles during blood cell development in metazoan species. [1][2][3][4] Mutations that disrupt the activity of AML1/Runx1 lead to hematopoietic disorders including myelodysplastic syndrome and acute myeloid leukemia (AML). 2,5 AML is the most frequent and debilitating form of leukemia with approximately a quarter million new cases diagnosed each year worldwide. The t(8;21) (q22;q22) chromosomal translocation that creates the AML1-ETO fusion product is present in 12%-15% of all cases of AML patients. The M2 subtype of AML carrying the AML1-ETO fusion protein is characterized by excessive production of granulocyte precursors. 6 Under normal conditions, AML1/RUNX1 (also known as core binding factor-␣, CBF␣) in association with CBF binds the enhancer core sequence, TGT/CGGT, to activate tissue-specific expression of a number of hematopoietic genes. 4 ETO (also known as MTG8) functions as a transcriptional repressor by recruiting a protein complex consisting of histone deacetylases (HDACs), the nuclear receptor co-receptor (N-CoR), mSin3A and the silencing mediator of retinoid and thyroid hormone receptor (SMRT). 7 ETO function has been implicated in the Notch pathway, 8 and it interacts with SON and TCF4. 9,10 The (8,21)(q22;q22) chromosomal aberration produces a potent oncogenic fusion protein consisting of most of the Runt domain of AML1 and nearly the complete sequence of ETO. 11 The general view among investigators in the field is that the AML1-ETO fusion product acts as a constitutive repressor form of AML1. 12,13 It has also been shown that this fusion protein has other activities in addition to interfering with AML1 function. 14,15 For example, AML1-ETO knock-in mouse embryos contain highly proliferative multilineage hematopoietic progenitors that are not found when either AML1 or CBF is disrupted. 12,14 Evidently, the full range of AML1-ETO target genes as well as components involved in the pathway, and their relevance to AML pathogenesis is not completely understood.To further our understanding of AML pathogenesis, additional animal models that allow in vivo genetic analysis are needed to complement studies in the existing mouse models. To this end, a Drosophila model is valuable due to the availability of facile genetic screens, a nearly complete collection of mutants, and advanced genetic technologies. T...