The DOT1L enzyme is hijacked by MLL-Fusion oncoproteins (MLL-FP) to aberrantly deposit H3K79methylation at key target genes to drive leukemogenesis. MLL-FP activity can be disrupted by blocking its chromatin occupancy with MLL-Menin inhibitors, or by blocking its biochemical activity through inhibition of DOT1L. Despite these inhibitors having potent anti-leukaemia effects, our understanding of how Menin and DOT1L contribute to MLL-FP function remains incomplete. Here, using functional genomics, we uncover a key role for the non-canonical Polycomb repressive complex 1.1 (PRC1.1) in the silencing of MLL-FP target genes required for the efficacy of Menin and DOT1L inhibitors across a range of in vitro and in vivo MLL-FP models. Mechanistically, Menin inhibition elicits a PRC1.1-dependent selective deposition of the repressive H2AK119ub mark at key MLL-FP target genes, whereas DOT1L inhibition leads to a more global increase in H2AK119ub. Consistent with these differences, we demonstrate that the treatment-induced increase in PRC1.1 activity is specifically associated with loss of H3K79me2 rather than eviction of the MLL-FP or reduction in transcription. In addition, temporal analyses after Menin inhibition revealed that H3K79me2 loss precedes the deposition of H2AK119ub and H3K27me3, which correlates with the gradual downregulation of transcription. Upon this switch in chromatin state, Polycomb target genes undergo stable PRC2-mediated repression, leading to proliferation arrest and the irreversible commitment of leukaemia cells towards differentiation even after early drug withdrawal. Importantly, we show that this interplay is conserved across diverse cell types suggesting a fundamental role for DOT1L in providing a memory of the active state to protect genes from rapid PRC1-mediated repression. Taken together, our findings highlight why DOT1L is hijacked in MLL-leukaemia and suggest that DOT1L is the missing link which balances the positive and negative forces of the MLL-Polycomb memory system.