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Updated: Jul 19, 2025

Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma
10:52

Tumor Engraftment in a Xenograft Mouse Model of Human Mantle Cell Lymphoma

Published on: March 30, 2018

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GSK-J4 Inhibition of KDM6B Histone Demethylase Blocks Adhesion of Mantle Cell Lymphoma Cells to Stromal Cells by

Laia Sadeghi1, Anthony P H Wright1

  • 1Division of Biomolecular and Cellular Medicine, Department of Laboratory Medicine, Karolinska Institutet, 17177 Stockholm, Sweden.

Cells
|August 11, 2023
PubMed

Insights

KDM6B histone demethylase promotes mantle cell lymphoma (MCL) cell adhesion and survival by activating NF-κB pathways. Inhibiting KDM6B may offer a new therapeutic strategy for MCL treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Malignant B-cells, including mantle cell lymphoma (MCL), rely on signaling pathways for survival and drug resistance.
  • NF-κB pathway dysregulation is common in MCL, but the precise mechanisms remain unclear.

Purpose of the Study:

  • To investigate the role of KDM6B histone demethylase in regulating MCL cell adhesion and NF-κB pathway activation.
  • To explore KDM6B as a potential therapeutic target in MCL.

Main Methods:

  • Utilized a co-culture model system of MCL cells and stromal cells.
  • Assessed KDM6B mRNA levels in adherent MCL cells.
  • Inhibited KDM6B activity using a selective inhibitor (GSK-J4) and siRNA-mediated knockdown.
  • Analyzed NF-κB pathway components, including RELA subunit, and target gene expression (e.g., IL-10, CCR7).

Main Results:

  • MCL cell adhesion to stromal cells correlated with increased KDM6B mRNA levels.
  • KDM6B inhibition reduced MCL cell adhesion.
  • KDM6B was essential for removing repressive chromatin marks (H3K27me3) and inducing NF-κB gene expression in adherent MCL cells.
  • GSK-J4 treatment decreased RELA protein levels and impaired its nuclear localization.
  • Specific target genes showed differential dependence on KDM6B and NF-κB for induction.

Conclusions:

  • KDM6B plays a crucial role in activating the NF-κB pathway at multiple levels in MCL.
  • This activation facilitates MCL cell adhesion, survival, and drug resistance.
  • KDM6B emerges as a promising novel therapeutic target for mantle cell lymphoma.
Keywords:
CCR7GSK-J4NF-κBhistone H3K27 methylationhistone H3K4 methylationmalignant B-cell adhesionmantle cell lymphomatumor microenvironment

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