Anti-Cancer Drug Discovery & Therapy (Track)

THE GENERATION OF AN ARTIFICIAL TRIPLE COMPLEX TO ORCHESTRATE THE EPIGENETIC REPROGRAMMING OF BPTF IN MLL2 MUTANT LYMPHOMAS

Sreeja Leelakumari, Oleksandr Yakovenko, Mor Ngom, Jianghong An, Andy J. Mungall, R. Keith Humphries and Steven J.M. Jones

BC Cancer Agency, Genome Sciences Centre, Vancouver, British Columbia, Canada

Abstract

Recurrent histone methyltransferase gene mutations in cancer cells provide a mechanism for genome wide alterations in chromatin regulation. In lymphomas, frequently mutated methyltransferase is MLL2, which writes activatory histone marks mediated by reader protein, BPTF. Loss of function mutations in MLL2 lead to concomitant increase in H3K4me1 levels, predicted to lead to inappropriate transcriptional silencing in lymphoma cells. We have computationally developed compounds that reprogram the H3K4me3 reader BPTF to recognize and bind to other H3K4 forms via the formation of a triple complex of H3K4me1, BPTF and the compound. The compounds were initially screened in silico followed by in vitro assays in DLBCL cell lines. Those compounds that showed MLL2 mutant-specific activity were subjected to pull-down assays which confirmed the reprogramming effects of compounds by altering the stability of BPTF complexes with peptides in different methylated states of H3K4 residue. In mouse xenograft model, these compounds had significant effect on tumour growth. To the best of our knowledge, this is the first example of small molecules modulating epigenomic programming by creating an artificial regulatory pathway in cancer cells, compensating for the lack of MLL2 methyltransferase activity, which is innovative and provides a new paradigm for the development of epigenomic targeting drugs.