TAMI-59. METABOLIC REGULATION OF THE EPIGENOME DRIVES LETHAL INFANTILE EPENDYMOMA

Abstract

Abstract Ependymomas are malignant glial tumors that occur throughout the central nervous system. Of the nine distinct molecular types of ependymoma, Posterior Fossa A(PFA) ependymomas, found in the hindbrain of infants and young children, are the most prevalent type. They rarely harbor recurrent somatic single nucleotide or copy number aberrations, but rather display epigenetic dysregulations. Transcriptional analyses show that PFAs, but not other molecular ependymoma variants, have elevated hypoxic signaling. We hypothesized that the metabolic environment of the developing human fetal hindbrain contributes to PFA ependymomas through the intermediary metabolic mechanism. Hypoxia microenvironment is essential for PFA survival and upholding their epigenetic dysregulation. Hypoxia blocks methyltransferase activity by upregulating EZHIPs expression and restricting SAM abundance. Fine-tuning the abundance of a-KG and acetyl-CoA, hypoxia fuels demethylase, and acetyltransferase activity which collectively resulting in H3K27 hypomethylation and hyperacetylation. Genome-wide essentially screen further underscore that minimal basal level of H3K27me3 is essential for PFA survival and further attenuation of H3K27me3 decreases the fitness of PFAs. PFA Ependymomas have a unique epigenome, suggesting a model in which they thrive in a narrow Goldilocks zone, with deviation to either increased or decreased H3K27me3 levels leading to diminished cellular fitness. PFAs are maintained under hypoxia, associated with restricted availability of specific metabolites to diminish histone methylation and increase histone demethylation and acetylation at H3K27. PFAs initiate from a cell lineage in the first trimester of human development that resides in restricted oxygen. Unlike other ependymomas, transient exposure of PFA cells to ambient oxygen induces irreversible cellular toxicity. PFA tumors exhibit a low basal level of H3K27me3 and, paradoxically, inhibition of H3K27 methylation specifically disrupts PFA growth. Microenvironmental regulation of PFA ependymoma epigenome appears to play a major role in tumorigenesis. Targeting metabolism and/or the epigenome presents a unique opportunity for rational therapy for infants with PFA ependymoma.