The HDAC8-U2AF1 Axis Dysregulates DNA Damage-Responsive RNA Splicing and Creates Targetable Vulnerabilities in Acute Myeloid Leukemia.

HDAC8 overexpression in AML impairs DNA repair by disrupting U2AF1 acetylation, leading to RNA splicing dysregulation and increased sensitivity to targeted therapies.

• Why it matters: AML remains highly lethal despite recent treatments, and understanding mechanisms of DNA repair defects could reveal new therapeutic vulnerabilities.
• What they did: Researchers analyzed AML patient datasets, demonstrated HDAC8’s role in impairing homologous recombination, and showed how HDAC8 regulates U2AF1 acetylation affecting DNA damage response and RNA splicing.
• The result: Targeting splicing with H3B-8800 and PARP inhibition with talazoparib reduced leukemia burden and stem cell activity, especially when combined, suggesting new biomarker-informed treatment strategies for HDAC8-high AML.