KMT2A oncoproteins induce epigenetic resistance to targeted therapies

Abstract

AbstractChromosomal translocations involving theLysine-Methyl-Tansferase-2A(KMT2A) locus generate potent oncogenes that cause highly aggressive acute leukemias1.KMT2Aand the most frequent translocation partners encode proteins that interact with DNA to regulate developmental gene expression2. KMT2A-oncogenic fusion proteins (oncoproteins) contribute to the epigenetic mechanisms that allowKMT2A-rearranged leukemias to evade targeted therapies. By profiling the oncoprotein-target sites of 34KMT2A-rearranged leukemia samples, we find that the genomic enrichment of oncoprotein binding is highly variable between samples. At high levels of expression, the oncoproteins preferentially activate either the lymphoid or myeloid lineage program depending on the fusion partner. These fusion-partner-dependent binding sites correspond to the frequencies of each mutation in acute lymphoid leukemia versus acute myeloid leukemia. By profiling a sample that underwent a lymphoid-to-myeloid lineage switching event in response to lymphoid-directed treatment, we find the global oncoprotein levels are reduced and the oncoprotein-target gene network changes. At lower levels of expression, the oncoprotein shifts to a non-canonical regulatory program that favors the myeloid lineage, and in a subset of resistant patients, the Menin inhibitor Revumenib induces a similar response. The dynamic shifts in KMT2A oncoproteins we describe likely contribute to epigenetic resistance ofKMT2A-rearranged leukemias to targeted therapies.