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Cancer-associated KBTBD4 mutations induce differentiation defects and confer a unique therapeutic vulnerability

Rohit Sivaprasad1, Kristijonas Žemaitis1, David Linfeldt1

  • 1Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.

Cancer Gene Therapy
|August 10, 2026
PubMed

Insights

Gain-of-function mutations in KBTBD4 drive embryonal brain tumors by disrupting stem cell differentiation. HDAC inhibitors like mocetinostat show promise in correcting these defects, offering new therapeutic avenues.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Stem Cell Biology

Background:

  • Epigenetic regulation is crucial for stem cell fate; its disruption can lead to cancer.
  • Mutations in ubiquitin ligase KBTBD4 targeting the CoREST complex are linked to high-risk embryonal brain tumors.
  • Modeling these early brain development tumors is challenging.

Purpose of the Study:

  • To investigate the tumorigenic potential of KBTBD4 mutations.
  • To model KBTBD4-driven tumorigenesis using hematopoietic stem and progenitor cells (HSPCs).
  • To identify therapeutic strategies targeting KBTBD4 mutations.

Main Methods:

  • Modeled KBTBD4 mutations in HSPCs, leveraging UM171's similar effect on CoREST degradation.
  • Utilized high-throughput screening to identify compounds disrupting mutant KBTBD4 activity.
  • Tested HDAC inhibitors, specifically mocetinostat, in the HSPC model.

Main Results:

  • KBTBD4 mutants caused expansion of immature stem/progenitor cells and impaired differentiation.
  • HDAC inhibitors were identified as agents that prevent mutant KBTBD4-CoREST interaction.
  • Mocetinostat treatment rescued differentiation defects in the HSPC model.

Conclusions:

  • KBTBD4 mutations promote tumorigenesis through CoREST complex disruption and impaired stem cell differentiation.
  • HDAC inhibitors represent a potential therapeutic vulnerability for KBTBD4-mutated tumors.
  • This study provides a model for investigating early brain development tumors and potential treatments.

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