The protein deacetylase HDAC10 controls DNA replication in malignant lymphoid cells

Area of Science:

• Epigenetics and Cancer Biology
• Molecular Oncology
• DNA Replication and Repair

Background:

• Histone deacetylases (HDACs) are epigenetic modifiers with largely unknown roles for HDAC10 in leukemia.
• Leukemia and lymphoma cells exhibit dependence on specific epigenetic regulators for survival.

Purpose of the Study:

• To elucidate the function of HDAC10 in acute B cell/T cell leukemia and lymphoma.
• To investigate the therapeutic potential of targeting HDAC10 in lymphoid malignancies.

Main Methods:

• Utilized cultured and primary human leukemia/lymphoma cells.
• Employed pharmacological inhibition of HDAC10 with PZ48.
• Assessed DNA damage, apoptosis markers (caspase-dependent), and gene expression (MYC-POLD1 axis).
• Validated in vivo efficacy in a Danio rerio model.

Main Results:

• HDAC10 catalytic activity is essential for leukemia and lymphoma cell survival.
• HDAC10 regulates MYC-dependent POLD1 transcription, impacting DNA polymerase processivity.
• HDAC10 inhibition by PZ48 induces DNA breaks and apoptosis in cancer cells.
• PZ48 demonstrates selectivity, sparing normal human blood cells.

Conclusions:

• HDAC10 plays a critical nuclear role in maintaining DNA replication and genome integrity via the MYC-POLD1 axis.
• Targeting HDAC10 represents a promising therapeutic strategy for lymphoid malignancies.
• The concept of "HDAC10ness" offers a novel mechanistic target for cancer treatment.