Acute leukaemias driven by MLL fusion oncoproteins (MLL-FP) are aggressive and often incurable malignancies that have attracted a substantial investment in therapies against essential oncogenic cofactors such as Menin, DOT1L and BRD4. The success of these novel drugs rests on a detailed understanding of the molecular mechanisms that regulate the recruitment and transcriptional activity of MLL-FP. Here, we develop a dynamic modular system to both map the genome-wide occupancy of MLL-FP in leukaemia cells and rapidly alter its oncogenic potential with an auxin-inducible degron. We use this system to define a core set of genes that are directly regulated by MLL-FP and show that the functional integrity of both DOT1L and Menin but not the BET bromodomain proteins is required for the chromatin localisation of MLL-FP. We find that perturbation of Menin surprisingly results in a dramatic loss of H3K79me2 at a small subset of loci directly linked to MLL-FP activity. To elucidate the regulation of H3K79methylation, we developed a novel CRISPR-screening method with a chromatin readout (CRISPR-ChIP) that unbiasedly identifies the non-redundant factors required for H3K79me2 and other chromatin modifications. Using CRISPR-ChIP in MLL-FP leukaemia, we uncover a functional partitioning of H3K79 methylation into two distinct regulatory units: an oncogenic DOT1L complex, where the malignant driver directs the catalytic activity of DOT1L at MLL-fusion target genes and a separate endogenous DOT1L complex, where catalytic activity is regulated by MLLT10. This functional demarcation has therapeutic implications that may enhance outcomes against MLL-FP leukaemia.