New study uncovers key mechanisms responsible for the transformation of adult progenitors into brain tumors

molecular mechanisms that cause some OPCs to become tumorigenic. By introducing specific genetic mutations, they discovered that a single mutation in a gene called Trp53, which normally suppresses tumor development, wasn’t enough to induce tumor formation in OPCs. However, when this mutation was combined with the overproduction of a growth factor called platelet-derived growth factor BB (PDGF-BB), the OPCs exhibited growth characteristics strikingly similar to tumor cells.

The study, published in the journal Neoplasia, revealed that only the OPCs with both the Trp53 mutation and PDGF-BB overproduction formed tumors when introduced into the brains of healthy mice, while those with only the Trp53 mutation did not. This finding prompted the researchers to further investigate what was driving this transformation.

“Our additional work identified that the overproduction of PDGF-BB in Trp53 mutant cells alters the growth characteristics of OPCs,” said first author Dennis Huang, a Ph.D. student in the CUNY Graduate Center Biology program working in Casaccia’s lab. “This alteration prevents their normal differentiation into myelin-forming oligodendrocytes by modifying certain histone tags.”

Specifically, in the nuclei of OPCs with both Trp53 mutation and PDGF-BB overexpression, the authors observed higher levels of H3K27me3 and lower levels of H4K20me3 histone tags, compared to cells bearing a single mutation. These results highlight the importance of specific epigenetic changes in driving the transformation of OPCs into gliomas.

They also showed that decreasing the levels of the H3K27me3 histone tag, using pharmacological inhibition, decreased the ability of the OPCs to divide but was not sufficient to stop the process of transformation. Overall, these results suggest that monotherapy with a single inhibitor of H3K27me3 needs to be combined with additional therapeutic strategy in glioma management.

The important discovery suggests that targeting additional histone post-translational modifications could be a promising approach in developing combination therapies for these as yet incurable brain tumors.