# DNTTIP1 drives leukaemogenesis through MiDAC‐mediated epigenetic silencing of BMF

## TL;DR

This study identifies DNTTIP1 as a key driver of leukemia by silencing BMF through epigenetic mechanisms, offering a new therapeutic strategy combining HDAC, BCL2, and PARP inhibitors.

## Contribution

The paper reveals DNTTIP1 as a novel epigenetic regulator in leukemia and proposes a triple-combination therapy with preclinical validation.

## Key findings

- DNTTIP1 recruits HDAC1/2 to silence BMF, promoting leukaemic cell survival.
- Pharmacological disruption of the DNTTIP1–HDAC1/2–BMF axis impairs leukaemogenesis.
- A triple combination of HDAC, BCL2, and PARP inhibitors shows synergistic anti-leukaemic effects.

## Abstract

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.

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.

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.

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.

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.

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.

DNTTIP1 cooperates with SP1 to recruit HDAC1/2, leading to BMF silencing and reduced competitive binding of BMF to BCL2.This suppresses autophagy and apoptosis, promoting leukaemic cell survival. Targeting the DNTTIP1‐HDAC1/2‐BMF axis reactivates BMF and induces anti‐leukaemic effects. The “HDACi+BCL2i+PARPi” triple combination shows potent efficacy and safety in preclinical models.