DNTTIP1 drives leukaemogenesis through MiDAC‐mediated epigenetic silencing of BMF

BACKGROUND: Acute leukaemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) within the mitotic deacetylase complex (MiDAC) as a previously unrecognised epigenetic regulator crucial for leukaemic cell survival and elucidate its mechanistic and translational significance. METHODS: Using cellular, biochemical, and genetic perturbations, coupled with validation in multiple in vivo leukaemia mouse models, we characterised DNTTIP1's role in acute leukaemia. An integrated multi-omics analysis incorporating RNA-seq, cleavage under targets and tagmentation (CUT&Tag) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed that DNTTIP1 recruits histone deacetylase 1/2 (HDAC1/2) to silence BCL2-modifying factor (BMF) and drive leukaemogenesis, validated by chromatin immunoprecipitation quantitative PCR (ChIP-qPCR). Drug synergy assays identify poly(ADP-ribose) polymerase (PARP)/HDAC/BCL2 inhibitor combinatorial efficacy. RESULTS: DNTTIP1 depletion impaired MiDAC recruitment in acute leukaemia, leading to histone H3 lysine 27 (H3K27) hyperacetylation at the BMF promoter and reactivating this effector. Upregulated BMF disrupted BCL2-mediated survival, triggering coordinated autophagy and apoptosis. Combined HDAC1/2 and BCL2 inhibition exerts synergistic anti-leukaemic effects, a therapeutic strategy currently under clinical evaluation. Further, PARP inhibition profoundly enhanced this synergy by impairing DNA damage repair, unveiling a novel triple-combination strategy. CONCLUSIONS: Our work defines the DNTTIP1‒HDAC1/2‒BMF axis as a pivotal epigenetic vulnerability in acute leukaemia and provides preclinical rationale for targeting this axis. These findings offer a validated biological framework for advancing this targeted combination therapy into clinical trials. KEY POINTS: DNTTIP1 is overexpressed in acute leukaemia and associated with poor prognosis. DNTTIP1 acts as a scaffold for the MiDAC complex, recruiting HDAC1/2 to silence BMF and inhibit leukaemic cell death. Pharmacological disruption of the DNTTIP1-HDAC1/2-BMF axis impairs leukaemogenesis.