Unravelling the vulnerability of the pons to developing Diffuse Midline Glioma (DMG)

Why certain regions of the brain are vulnerable to oncogenic transformation at critical periods of development is largely unknown.

This is also the case for diffuse midline glioma, H3K27M mutant, a completely fatal and aggressive brain tumor that occurs in the pons, during early childhood.

My hypothesis is that the roots and origins of DMG, H3K27M mutant, are to be found by dissecting normal pons development during a time period that is critical to tumor development.

This project will aim to show that a specific cell population within the pons relies on methylation of the H3K27 histone mark, a process that is blocked by the H3K27M mutation locking the DMG cell of origin into a primitive state that favors self-renewal over differentiation.

My preliminary data support this observation as only a portion of Sox2+ neural stem cell progenitors have increased H3K27me3 in the postnatal day 2 mouse pons.

Building on this, we will show that pons-specific microglia are essential for adequate lineage differentiation of H3K27me3+ cells and that these important signals are subverted by the tumor during this critical period. We will  explore why the pons is vulnerable to developing such an aggressive brain tumour during early childhood.

It will fill a large gap in the understanding of the spatial temporal dynamics of childhood brain tumors, as well as providing new knowledge about normal pons developmental during this critical period of development.