The use of Menin inhibitors (MENi) to treat Acute Myeloid Leukemia (AML) has shown great clinical promise resulting in several phase 1/2 clinical trials. Acquired resistance mechanisms to MENi through mutations in MEN1 have been identified, highlighting the need to further improve efficacy of treatment. We have previously shown that Leukemic Stem Cells (LSCs) are reliant on HBO1, a member of the MYST2 histone acetyltransferase complex. Both genetic knockout and small molecule inhibition of HBO1 drive the differentiation and cell death of LSCs and leukemic blasts. Here, we have found that mouse and human AML cells harbouring KMT2A rearrangements (MLL-r) are highly sensitive to the combination of MYST and Menin inhibition. Combination therapy resulted in the rapid loss of expression of leukemia driver genes MEIS1 and HOXA9 before growth arrest and cell death. We are using chromatin immunoprecipitation sequencing to understand how synergy between MYST and Menin alters histone acetylation and chromatin of marks deposited by MYST members HBO1 and MOZ/MORF across the genome and at loci essential to leukemogenesis. These data reveal a new synergy between two chromatin-modifying complexes to sustain MLL-r leukemia. Ultimately, this work will be used to inform future clinical trials exploring Menin and MYST inhibition.