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

Sivaprasad, Rohit LU orcid ; Žemaitis, Kristijonas LU ; Linfeldt, David LU ; Ghosh, Sudip LU ; de Snaijer, Anne ; Magnusson, Mattias LU ; Ek, Fredrik LU orcid ; Hansson, Jenny LU orcid and Subramaniam, Agatheeswaran LU (2026) In Cancer Gene Therapy
Abstract

Epigenetic regulation governs stem cell fate and perturbations in these mechanisms often lead to tumor development. The CoREST complex, a critical regulator of neural and hematopoietic stem cell differentiation, is recurrently targeted by gain of function mutations in the ubiquitin ligase KBTBD4 in high-risk embryonal brain tumors. However, the tumorigenic potential of these mutations remains unresolved partly due to the challenges in modeling tumors that arise during early brain development. We and others recently demonstrated that small molecule UM171 mimics KBTBD4 mutations by promoting robust CoREST degradation and expansion of hematopoietic stem cells. Leveraging this mechanistic similarity, we modeled KBTBD4 mutations in... (More)

Epigenetic regulation governs stem cell fate and perturbations in these mechanisms often lead to tumor development. The CoREST complex, a critical regulator of neural and hematopoietic stem cell differentiation, is recurrently targeted by gain of function mutations in the ubiquitin ligase KBTBD4 in high-risk embryonal brain tumors. However, the tumorigenic potential of these mutations remains unresolved partly due to the challenges in modeling tumors that arise during early brain development. We and others recently demonstrated that small molecule UM171 mimics KBTBD4 mutations by promoting robust CoREST degradation and expansion of hematopoietic stem cells. Leveraging this mechanistic similarity, we modeled KBTBD4 mutations in hematopoietic stem and progenitor cells (HSPCs) and found that mutants induced expansion of immature stem and progenitor populations and impaired lineage differentiation. High-throughput screening identified HDAC inhibitors as specific agents that disrupt mutant KBTBD4 activity, by preventing interaction with the CoREST complex. Using our HSPC model, we demonstrated that the class I HDAC inhibitor mocetinostat alleviated differentiation defects caused by KBTBD4 mutations. Together, these findings reveal the tumorigenic mechanism of KBTBD4 mutations and uncover therapeutic vulnerabilities that may be exploited for clinical applications.

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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
in
Cancer Gene Therapy
publisher
Nature Publishing Group
external identifiers
  • pmid:42576054
  • scopus:105047003077
ISSN
1476-5500
DOI
10.1038/s41417-026-01068-x
language
English
LU publication?
yes
additional info
© 2026. The Author(s).
id
d1610e59-e554-4226-86ac-0fcd8995a308
date added to LUP
2026-08-11 08:50:03
date last changed
2026-09-11 04:00:55
@article{d1610e59-e554-4226-86ac-0fcd8995a308,
  abstract     = {{<p>Epigenetic regulation governs stem cell fate and perturbations in these mechanisms often lead to tumor development. The CoREST complex, a critical regulator of neural and hematopoietic stem cell differentiation, is recurrently targeted by gain of function mutations in the ubiquitin ligase KBTBD4 in high-risk embryonal brain tumors. However, the tumorigenic potential of these mutations remains unresolved partly due to the challenges in modeling tumors that arise during early brain development. We and others recently demonstrated that small molecule UM171 mimics KBTBD4 mutations by promoting robust CoREST degradation and expansion of hematopoietic stem cells. Leveraging this mechanistic similarity, we modeled KBTBD4 mutations in hematopoietic stem and progenitor cells (HSPCs) and found that mutants induced expansion of immature stem and progenitor populations and impaired lineage differentiation. High-throughput screening identified HDAC inhibitors as specific agents that disrupt mutant KBTBD4 activity, by preventing interaction with the CoREST complex. Using our HSPC model, we demonstrated that the class I HDAC inhibitor mocetinostat alleviated differentiation defects caused by KBTBD4 mutations. Together, these findings reveal the tumorigenic mechanism of KBTBD4 mutations and uncover therapeutic vulnerabilities that may be exploited for clinical applications.</p>}},
  author       = {{Sivaprasad, Rohit and Žemaitis, Kristijonas and Linfeldt, David and Ghosh, Sudip and de Snaijer, Anne and Magnusson, Mattias and Ek, Fredrik and Hansson, Jenny and Subramaniam, Agatheeswaran}},
  issn         = {{1476-5500}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Cancer Gene Therapy}},
  title        = {{Cancer-associated KBTBD4 mutations induce differentiation defects and confer a unique therapeutic vulnerability}},
  url          = {{http://dx.doi.org/10.1038/s41417-026-01068-x}},
  doi          = {{10.1038/s41417-026-01068-x}},
  year         = {{2026}},
}