Project description:The ETO-family transcriptional corepressors, including ETO, ETO2 and MTGR1, are all involved in leukemia-causing chromosomal translocations. In every case, an ETO-family corepressor acquires a DNA-binding domain (DBD) to form a typical transcription factor – the DBD binds to target genes, while the ETO moiety contributes essentially to its transcriptional property. A direct comparative study of these “homologous” fusion transcription factors may clarify their similarities and differences in regulating transcription and leukemogenesis. Here, we performed a side-by-side comparison between AML1-ETO and ETO2-GLIS2, the most common fusion proteins in the M2 and M7 subtypes of acute myeloid leukemia, respectively, by inducible expression of them in U937 leukemia cells. We found that, although AML1-ETO and ETO2-GLIS2 can use their own DBDs (i.e., the Runt domain of AML1 and the zinc finger domain of GLIS2) to bind DNA, they actually share a large proportion of genome-wide binding regions dependent on other cooperative transcription factors such as ETS- and CEBP-family proteins. Functionally, AML1-ETO acts as either transcriptional repressor or activator, whereas ETO2-GLIS2 mainly acts as an activator. The repressor-versus-activator functions of AML1-ETO is determined by the abundance of cooperative transcription factors/cofactors on the target genes. Through these mechanisms, AML1-ETO and ETO2-GLIS2 differentially regulate several key transcription factors that are essential for myeloid differentiation. Indeed, AML1-ETO inhibits myeloid differentiation of U937 cells, whereas ETO2-GLIS2 facilitates it. Taken together, this study is the first direct comparative study between AML1-ETO and ETO2-GLIS2 in the same cellular context, and the results provide new insights into the context-dependent transcriptional regulatory mechanisms that may underlie how these seemingly “homologous” fusion transcription factors exert distinct functions to drive different subtypes of leukemia.

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A direct comparison between AML1-ETO and ETO2-GLIS2 leukemia fusion proteins reveals distinct transcriptional properties and context-dependent binding and regulation of target genes

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