Alternative Lengthening of Telomeres in Pediatric High-Grade Glioma and Therapeutic Implications

Abstract

Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma (DIPG), are highly aggressive tumors with dismal prognoses despite multimodal therapy including surgery, radiation therapy, and chemotherapy. To achieve cellular immortality cancer cells must overcome replicative senescence and apoptosis by activating telomere maintenance mechanisms (TMMs) through the reactivation of telomerase activity or using alternative lengthening of telomere (ALT) pathways. Although the ALT phenotype is more prevalent in pHGGs compared to adult HGGs, the molecular pathway and the prognostic significance of ALT activation are not well understood in pHGGs. Here, we report the heterogeneity of TMM in pHGGs and their association with genetic alterations. Additionally, we show that sensitivity to the protein kinase ataxia telangiectasia- and RAD3-related protein (ATR) inhibitor and the ATR downstream target CHK1 is not specific to pHGG ALT-positive cells. Together, these findings underscore the need for novel therapeutic strategies to target ALT in pHGG tumors.

The Role of Glia Telomere Dysfunction in the Pathogenesis of Central Nervous System Diseases

“…Importantly, recent findings in pediatric high-grade gliomas (pHGGs) like diffuse intrinsic pontine glioma (DIPG), and telomere maintenance mechanisms exhibit a noteworthy heterogeneity. The coexistence of telomerase and ALT pathways within the same tumor underscores the intricate nature of intratumoral heterogeneity in telomere length and maintenance mechanisms [ 62 ].…”