Pediatric Diffuse Midline Glioma H3K27-Altered: From Developmental Origins to Therapeutic Challenges.

Autor: Mandorino, Manuela, Maitra, Ahana, Armenise, Domenico, Baldelli, Olga Maria, Miciaccia, Morena, Ferorelli, Savina, Perrone, Maria Grazia, Scilimati, Antonio
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Zdroj: Cancers; May2024, Vol. 16 Issue 10, p1814, 13p
Abstrakt: Simple Summary: Diffuse midline glioma (DMG), especially diffuse intrinsic pontine glioma (DIPG), is a deadly pediatric brain tumor that is difficult to diagnose and lacks any real treatment. These tumors often affect deep midline brain structures in young children, suggesting a connection to early brain development and differentiation. The H3K27M mutation triggers DIPG, impacting gene expression and brain development. Despite targeted drug interventions for gene mutations, the grim prognosis of the disease remains unaltered. DIPG patients typically succumb to the illness within 12 to 18 months post-diagnosis. Our review found over 85% of DIPG tumors have the K27M mutation in histone genes, driving abnormal growth. This mutation affects crucial brain processes, including the epithelial–mesenchymal transition pathway, potentially explaining differences between gliomas with and without K27M. The timing of these mutations is not known. One idea is that these mutations might have started during the early development of the brain before birth. Diffuse intrinsic pontine glioma (DIPG), now referred to as diffuse midline glioma (DMG), is a highly aggressive pediatric cancer primarily affecting children aged 4 to 9 years old. Despite the research and clinical trials conducted to identify a possible treatment for DIPG, no effective drug is currently available. These tumors often affect deep midline brain structures in young children, suggesting a connection to early brain development's epigenetic regulation targets, possibly affecting neural progenitor functions and differentiation. The H3K27M mutation is a known DIPG trigger, but the exact mechanisms beyond epigenetic regulation remain unclear. After thoroughly examining the available literature, we found that over 85% of DIPG tumors contain a somatic missense mutation, K27M, in genes encoding histone H3.3 and H3.1, leading to abnormal gene expression that drives tumor growth and spread. This mutation impacts crucial brain development processes, including the epithelial–mesenchymal transition (EMT) pathway, and may explain differences between H3K27M and non-K27M pediatric gliomas. Effects on stem cells show increased proliferation and disrupted differentiation. The genomic organization of H3 gene family members in the developing brain has revealed variations in their expression patterns. All these observations suggest a need for global efforts to understand developmental origins and potential treatments. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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