December
2,
2022
(Drug ACTION Specific Seminar)
Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. The exact role of H3K27M in promoting tumorigenesis and whether it is a relevant therapeutic target is unclear. Oligodendrocyte progenitor cells (OPCs) in the brainstem are thought to be candidate cells-of-origin for DMG as most of the tumor cells of DMGs have an OPC signature. There have been several genetically engineered mouse models of DMG, some requiring PDGFRA signaling for DMG tumorigenesis, and some do not.
Our lab has used the RCAS/Tv-a avian retroviral system to generate DMG at the postnatal brainstem. We have explored several candidate cells-of-origin expressing Nestin, Olig2, Pax3, and GFAP. All our successful modeling efforts required overexpression of the PDGFA or PDGFB ligand together with H3.3K27M or H3.1K27M. We have noted that the effects of H3.3K27M are cell-of-origin dependent but inhibition of inflammation by H3K27M was seen in more than one model. Aggressive tumors with a short tumor latency require either p53 loss or PTEN loss or both. With the recent identification of EZHIP or CATACOMB, as an endogenous gene that can also exhibit ‘H3K27M’ activity, and is found in both PFA ependymoma and DMG, we have performed studies to explore its role in tumorigenesis with the RCAS/Tv-a system. As a control we used an M406K LOF Mutant of EZHIP. We observed similar results with EZHIP and H3K27M, that I will highlight. Our results suggest that p53 status may have a more pronounced role on tumorigenesis that the presence of H3K27M or EZHIP. Furthermore, we identify the CDKN2A locus as an important locus that is repressed by H3.3K27M. Interestingly, when the CDKN2A locus is deleted, the effects of H3.3K27M on tumor latency are further diminished.
More recently we have also performed single cell RNAseq on the murine DMG tumors that I will describe. This analysis has highlighted the paucity of T cells, the presence of a population of myeloid cells, as well as tumor cells that are cycling or quiescent or hypoxic. In summary, our results suggest that H3K27M may contribute to tumorigenesis by inhibiting inflammation, and this may be one reason why it is an important therapeutic target in DMG.
Hosted by Lara Collier
