Functional consequences of HDI1 and CIC mutations on the cells of origin of oligodendrogliomas
Oligodendrogliomas are primary tumours of the central nervous system with morphological characteristics of oligodendrocytes. It has been proposed that the precursors of oligodendrocytes or OPC, for Oligodendrocyte Progenitor Cells, are the cells that cause oligodendrogliomas. They are generated from neural stem cells during development. At birth, the latter differentiate into oligodendrocytes, the cells responsible for the myelination of neurons. OPC persist in the adult brain where they are the most proliferative cell type.
The genetics of oligodendrogliomas in humans is well known and shows frequent mutations in several genes. For example, the mutation of the enzyme Isocitrate Dehydrogenase 1 (IDH1R132H) is found in 100% of oligodendrogliomas. In physiological condition, IDH1 allows the conversion of isocitrate to a-cetoglutarate, but when mutated, it acquires a new function: that of reducing a-cetoglutarate to D-2-hydroxyglutarate, an oncometabolite that accumulates in cells. Similarly, all oligodendrogliomas have a co-deletion of chromosomes 1p and 19q. It is interesting to note that the 19q arm codes for the CIC (Capicua) protein which is found mutated in 50-70% of oligodendrogliomas. Physiologically, CIC decreases cell proliferation and promotes cell differentiation; thus its mutation in oligodendrogliomas results in a non-functional protein.
New therapies are needed for oligodendrogliomas, especially for the more aggressive forms that can progress to glioblastoma. Although the mutations present in human tumours are well characterized, the research community does not have a study model for understanding the formation and development of oligodendrogliomas. Possessing in vivo models to study the initiation, formation and progression of oligodendrogliomas remains a major challenge in order to discover functional treatments.
Emmanuelle Huillard’s research team proposes to create and characterize a new in vivo model to induce HDI1 and CIC mutations in OPC. Our working hypothesis is that the synergy of these mutations will induce an increase in proliferation to the detriment of OPC differentiation, two behaviours that are modified during tumorigenesis.
By developing and describing this model, which summarizes the genetics of human oligodendrogliomas, we hope to provide the scientific community with a biological tool for understanding the formation of these tumors as well as for preclinical studies.
post-PhD, Emmanuelle Huillard’s research team