Genome-wide studies identify a novel interplay between AML1 and AML1/ETO in t(8;21) acute myeloid leukemia

Abstract

The AML1/ETO fusion protein is essential to the development of t(8;21) acute myeloid leukemia (AML) and is well recognized for its dominant-negative effect on the coexisting wild-type protein AML1. However, the genome-wide interplay between AML1/ETO and wild-type AML1 remains elusive in the leukemogenesis of t(8;21) AML. Through chromatin immunoprecipitation sequencing and computational analysis, followed by a series of experimental validations, we report here that wild-type AML1 is able to orchestrate the expression of AML1/ETO targets regardless of being activated or repressed; this is achieved via forming a complex with AML1/ETO and via recruiting the cofactor AP-1 on chromatin. On chromatin occupancy, AML1/ETO and wild-type AML1 largely overlap and preferentially bind to adjacent and distinct short and long AML1 motifs on the colocalized regions, respectively. On physical interaction, AML1/ETO can form a complex with wild-typeAML1 on chromatin, and the runt homology domain of both proteins are responsible for their interactions. More importantly, the relative binding signals of AML1 and AML1/ETO on chromatin determine which genes are repressed or activated by AML1/ETO. Further analysis of coregulators indicates that AML1/ETO transactivates gene expression through recruiting AP-1 to the AML1/ETO-AML1 complex. These findings enrich our knowledge of understanding the significance of the interplay between the wild-type protein and the oncogenic fusion protein in the development of leukemia.