Related Experiment Video

Updated: Apr 18, 2026

Live-3D-Cell Immunocytochemistry Assays of Pediatric Diffuse Midline Glioma
09:06

Live-3D-Cell Immunocytochemistry Assays of Pediatric Diffuse Midline Glioma

Published on: November 11, 2021

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H3 dopaminylation and CaMKII modulate diffuse midline glioma response to CDK9 inhibition

Rebecca L Murdaugh1,2,3,4, Brittany R Eberl1,2,3,4, Rosemary U Richard1,2,3,4

  • 1Department of Neurosurgery, Baylor College of Medicine, Houston, TX, USA.

Biorxiv : the Preprint Server for Biology
|April 17, 2026
PubMed

Insights

Combining CDK9 inhibitors with SSRIs synergistically reduces diffuse midline glioma growth by altering H3 dopaminylation and repressing gene transcription. This suggests targeting monoamine neurotransmitter pathways offers a novel therapeutic strategy for gliomas.

Area of Science:

  • Neuro-oncology
  • Epigenetics
  • Molecular Biology

Background:

  • Aberrant neurotransmitter signaling and transcriptional dysregulation are key features of gliomagenesis.
  • Monoamine neurotransmitters, like dopamine and serotonin, signal through GPCRs and epigenetically via histone modifications.
  • Diffuse midline glioma (DMG) presents significant therapeutic challenges.

Purpose of the Study:

  • To investigate the mechanisms of crosstalk between monoamine neurotransmitter signaling, histone H3 dopaminylation, and RNA polymerase II (Pol2) transcription in DMG.
  • To evaluate the synergistic effects of CDK9 inhibitors and selective serotonin reuptake inhibitors (SSRIs) on DMG growth.
  • To identify signaling pathways involved in response and resistance to CDK9 inhibition in DMG.

Main Methods:

  • Co-treatment of DMG models with Pol2-targeting CDK9 inhibitors and FDA-approved SSRIs.
  • Analysis of H3 dopaminylation patterns and gene transcription.
  • Phospho-proteomic analyses to identify signaling pathway activation.

Main Results:

  • Co-treatment with CDK9 inhibitors and SSRIs synergistically reduced DMG growth.
  • This combination therapy altered H3 dopaminylation and repressed synaptic and neurodevelopmental gene transcription, overcoming CDK9 inhibitor resistance.
  • CDK9 inhibitor monotherapy activated pro-survival CaMKII signaling, which was suppressed by co-treatment with neuromodulatory drugs.

Conclusions:

  • H3 dopaminylation and neurotransmitter signaling play critical roles in regulating gene expression in DMG.
  • Targeting monoamine neurotransmitter pathways, in combination with CDK9 inhibitors, represents a promising therapeutic strategy for diffuse midline glioma.
  • Neuromodulatory drugs can overcome resistance to CDK9 inhibitors by suppressing pro-survival signaling pathways.

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