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

Monoamine neurotransmitters such as dopamine and serotonin primarily activate GPCRs but can also function epigenetically as histone H3 modifications. Here, we uncover mechanisms of crosstalk between monoamine neurotransmitter signaling, H3 dopaminylation, and RNA polymerase II (Pol2) transcription in diffuse midline glioma (DMG).

We find that co-treatment with Pol2 targeting CDK9 inhibitors (CDK9i) and FDA approved neuropsychiatric drugs, including selective serotonin reuptake inhibitors (SSRIs), synergistically reduces DMG growth. Mechanistically, CDK9i+SSRI treatment alters H3 dopaminylation patterns and represses synaptic and neurodevelopmental gene transcription associated with CDK9i resistance. Further phospho-proteomic analyses show that CDK9i monotherapy activates pro survival CaMKII signaling, which can be suppressed by co-treatment with neuromodulatory drugs.