Related Experiment Video

Updated: Sep 21, 2025

Direct Measurement of KDM1A Target Engagement Using Chemoprobe-based Immunoassays
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Histone demethylase KDM4C is a functional dependency in JAK2-mutated neoplasms

Philipp Ernst1,2, Tina M Schnöder3, Nicolas Huber3

  • 1Klinik für Innere Medizin 2, Hämatologie und Onkologie, Universitätsklinikum Jena, Jena, Germany.

Leukemia
|June 2, 2022
PubMed

Insights

Targeting KDM4C offers a new therapeutic strategy for JAK2-mutated myeloid neoplasms. Inhibiting KDM4C reduces malignant cell proliferation and improves survival, independent of JAK-inhibitor treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Hematology

Background:

  • Janus kinase 2 (JAK2) mutations are common in aging and myeloid neoplasms.
  • JAK-inhibitors manage hyperinflammation but do not eliminate the malignant clone.

Purpose of the Study:

  • To identify genetic vulnerabilities in JAK2-mutated cells.
  • To evaluate KDM4C as a potential therapeutic target.

Main Methods:

  • Genetic inactivation of KDM4C in human and murine JAK2-mutated cells.
  • Assessment of cell competition, proliferation, and disease penetrance in xenograft models.
  • Analysis of histone methylation and gene expression changes.

Main Results:

  • KDM4C was identified as a selective genetic dependency in JAK2-mutated cells.
  • KDM4C inactivation led to reduced proliferation and cell competition.
  • Disease penetrance decreased, and survival improved in xenograft models.
  • KDM4C deletion induced cellular senescence via altered histone methylation and gene expression.

Conclusions:

  • KDM4C is a specific dependency in JAK2-mutated cells, crucial for oncogenic signaling.
  • Targeting KDM4C represents a promising therapeutic strategy for JAK2-mutated myeloid neoplasms.
  • KDM4C inhibition prevents senescence escape in malignant cells.

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