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<p>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 <i>Danio rerio</i> 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.</p><p></p>

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The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月29日

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  • Andreas O. Mieland,
  • Giuseppe Petrosino,
  • Mario Dejung,
  • Jia-Xuan Chen,
  • Amitkumar Fulzele,
  • Fereshteh Mahmoudi,
  • Jia-Wey Tu,
  • Al-Hassan M. Mustafa,
  • Yanira Zeyn,
  • Christoph Hieber,
  • Matthias Bros,
  • Tina M. Schnöder,
  • Florian H. Heidel,
  • Sara Najafi,
  • Ina Oehme,
  • Ilse Hofmann,
  • Mike Schutkowski,
  • Sebastian Hilscher,
  • Christian Kosan,
  • Falk Butter,
  • Sanil Bhatia,
  • Wolfgang Sippl,
  • Oliver H. Krämer

摘要

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.