The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells

Histone deacetylases (HDACs) are a family of 18 epigenetic modifiers. Targets and cancer-relevant functions of HDAC10 in leukemia cells are enigmatic. We used flow cytometry, confocal immunofluorescence, single-cell DNA electrophoresis, global RNA-sequencing, mass spectrometry-based proteomics, and quantitative measurement of protein acetylation sites to evaluate how HDAC10 controls cancer-relevant signaling pathways in leukemia cells. We demonstrate that a subset of human cultured and primary acute B-cell/T-cell leukemia and lymphoma cells require HDAC10 for their survival. In such cells, HDAC10 controls a MYC-dependent transcriptional induction of the DNA polymerase subunit POLD1. Consequently, inhibition of HDAC10 halts cells in the S and G2/M phases of the cell cycle and causes DNA breaks, and an accumulation of poly-ADP-ribose chains indicating unresolved DNA damage. These processes culminate in caspase-dependent apoptosis. We reveal that HDAC10 has a nuclear function controlling the MYC-POLD1 axis. HDAC10 maintains the processivity of DNA replication and genome integrity in leukemic cell subtypes. This mechanistically defined HDAC10ness could prospectively be exploited as treatment option. We performed gene expression profiling to investigate the impact of inhibition of HDAC10 by PZ48 in RS4-11 cells.