A G-Quadruplex-Forming Rna Aptamer Binds To The Mtg8 Tafh Domain And Dissociates The Leukemic Aml1-Mtg8 Fusion Protein From Dna

MTG8(RUNX1T1) is a fusion partner ofAML1 (RUNX1)in the leukemic chromosome translocation t(8;21). TheAML1-MTG8fusion gene encodes a chimeric transcription factor. One of the highly conserved domains of MTG8 is TAFH which possesses homology with human TAF4 [TATA-box binding protein-associated factor]. To obtain specific inhibitors of the AML1-MTG8 fusion protein, we isolated RNA aptamers against the MTG8 TAFH domain using systematic evolution of ligands by exponential enrichment. All TAF aptamers contained guanine-rich sequences. Analyses of a TAF aptamer by NMR, CD, and mutagenesis revealed that it forms a parallel G-quadruplex structure in the presence of K+. Furthermore, the aptamer could bind to the AML1-MTG8 fusion protein and dissociate the AML1-MTG8/DNA complex, suggesting that it can inhibit the dominant negative effects of AML1-MTG8 against normal AML1 function and serve as a potential therapeutic agent for leukemia.