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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
Summary
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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