The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells
Histone deacetylases (HDACs) comprise a family of 18 epigenetic modifiers. The biologically relevant functions of HDAC10 in leukemia cells are enigmatic. We demonstrate that human cultured and primary acute B cell/T cell leukemia and lymphoma cells require the catalytic activity of HDAC10 for their survival. In such cells, HDAC10 controls a MYC-dependent transcriptional induction of the DNA polymerase subunit POLD1. Consequently, pharmacological inhibition of HDAC10 causes DNA breaks and an accumulation of poly-ADP-ribose chains. These processes culminate in caspase-dependent apoptosis. PZ48 does not damage resting and proliferating human normal blood cells. The in vivo activity of PZ48 against ALL cells is verified in a Danio rerio model. These data reveal a nuclear function for HDAC10. HDAC10 controls the MYC-POLD1 axis to maintain the processivity of DNA replication and genome integrity. This mechanistically defined "HDAC10ness" may be exploited as treatment option for lymphoid malignancies.
Authors
- Mario Dejung (ORCID: https://orcid.org/0000-0002-0509-0207)
- Christoph Hieber (ORCID: https://orcid.org/0009-0002-3343-4203)
- Ina Oehme (ORCID: https://orcid.org/0000-0002-0827-2356)
- Andreas O. Mieland (ORCID: https://orcid.org/0000-0002-8672-0708)
- Jia‐Xuan Chen (ORCID: https://orcid.org/0000-0002-3671-553X)
- Fereshteh Mahmoudi
- Falk Butter (ORCID: https://orcid.org/0000-0002-7197-7279)
- Tina M. Schnoeder (ORCID: https://orcid.org/0000-0002-6351-4119)
- Sanil Bhatia (ORCID: https://orcid.org/0000-0001-6494-7744)
- Ilse Hofmann (ORCID: https://orcid.org/0000-0002-3586-5050)
- Christian Kosan (ORCID: https://orcid.org/0000-0002-8387-3653)
- Oliver Holger Krämer (ORCID: https://orcid.org/0000-0003-3973-045X)
- Yanira Zeyn (ORCID: https://orcid.org/0000-0002-2501-8149)
- Wolfgang Sippl (ORCID: https://orcid.org/0000-0002-5985-9261)
- Mike Schutkowski (ORCID: https://orcid.org/0000-0003-0919-7076)
- Matthias Bros (ORCID: https://orcid.org/0000-0002-4662-0542)
- Giuseppe Petrosino (ORCID: https://orcid.org/0000-0002-2835-4308)
- Sara Najafi (ORCID: https://orcid.org/0000-0003-1218-1817)
- Jia‐Wey Tu
- Sebastian Hilscher (ORCID: https://orcid.org/0009-0003-0611-7365)
- Florian Heinrich Heidel (ORCID: https://orcid.org/0000-0003-2438-1955)
Institutions
- German Cancer Research Center (DE)
- Johannes Gutenberg University Mainz (DE)
- Heidelberg University (DE)
- Medizinische Hochschule Hannover (DE)
- University Medical Center of the Johannes Gutenberg University Mainz (DE)
- National Center for Tumor Diseases (DE)
- Hopp Children's Cancer Center Heidelberg (DE)
- Leibniz Institute on Aging - Fritz Lipmann Institute (FLI) (DE)
- Institute of Molecular Biology (DE)
- Deutsches Konsortium für Translationale Krebsforschung (DE)
- Heinrich Heine University Düsseldorf (DE)
- Martin Luther University Halle-Wittenberg (DE)
- Friedrich Schiller University Jena (DE)
- Aswan University (EG)
Publication Details
- Journal
- Leukemia
- Published
- 2025-04-29
- DOI
- https://doi.org/10.1038/s41375-025-02612-8
- Citations
- 5
- Primary Topic
- Histone Deacetylase Inhibitors Research
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- Alexander von Humboldt-Stiftung
- Deutscher Akademischer Austauschdienst
- Deutsche Forschungsgemeinschaft
- Hector Stiftung