Journal
DEVELOPMENT
Volume 132, Issue 10, Pages 2263-2272Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.01824
Keywords
AML1 (RUNX 1); AML1-ETO; MTG8; lozenge; CBF beta; Drosophila eye; RUNX1T1
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Funding
- NCI NIH HHS [R01 CA087379] Funding Source: Medline
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The human translocation (t8;21) is associated with similar to 12 % of the cases of acute myelogenous leukemia. Two genes, AML1 and ETO, are fused together at the translocation breakpoint, resulting in the expression of a chimeric protein called AML1-ETO. AML1-ETO is thought to interfere with normal AML1 function, although the mechanism by which it does so is unclear. Here, we have used Drosophila genetics to investigate two models of AML1-ETO function. In the first model, AML1-ETO, is a constitutive transcriptional repressor of AML1 target genes, regardless of whether they are normally activated or repressed by AML1 In the second model, AML1-ETO dominantly interferes with AML1 activity by, for example, competing for a common co-factor. To discriminate between these models, the effects of expressing AML1-ETO were characterized and compared with loss-of-function phenotypes of lozenge (lz), an AML1 homolog expressed during Drosophila eye development. We also present results of genetic interaction experiments with AML1 co-factors that are not consistent with AML1-ETO behaving as a dominant-negative factor. Instead, our data suggest that AML1-ETO acts as a constitutive transcriptional repressor.
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