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. Overall design: We performed gene expression profiling to investigate the impact of inhibition of HDAC10 by PZ48 in RS4-11 cells.