Dysregulated purine metabolism in DIPG reveals new treatment strategies with old drugs [RNA-seq]

Over 80% of DIPGs possess a H3K27M mutation. To identify metabolic vulnerabilities linked to this mutation, we utilized a multi-omics approach in H3K27M-expressing cells, patient-derived cell lines, and mouse models.

We show that by reprogramming chromatin landscape the mutation aberrantly induces NFI transcriptional activity, leading to misregulated purine and folate metabolism. Specifically, the mutation amplifies purine biosynthesis and degradation via the enzymes ATIC and PNP, respectively. Unregulated purine degradation makes DIPGs reliant on purine biosynthesis and targeting ATIC reduced tumor progression and improved survival in mice.