ZFTA-RELA ependymomas make itaconate to epigenetically drive fusion expression

ZFTA-RELA⁺ ependymomas are malignant brain tumours defined by fusions formed between the putative chromatin remodeller ZFTA and the NF-κB mediator RELA¹. Here we show that ZFTA-RELA⁺ cells produce itaconate, a key macrophage-associated immunomodulatory metabolite². Itaconate is generated by cis-aconitate decarboxylase 1 (ACOD1; also known as IRG1). However, the production of itaconate by tumour cells and its tumour-intrinsic role are not well established. ACOD1 is upregulated in a ZFTA-RELA-dependent manner. Functionally, itaconate enables a feed-forward system that is crucial for the maintenance of pathogenic ZFTA-RELA levels. Itaconate epigenetically activates ZFTA-RELA transcription by enriching for activating H3K4me3 via inhibition of the H3K4 demethylase KDM5. ZFTA-RELA⁺ tumours enhance glutamine metabolism to supply carbons for itaconate synthesis. Antagonism of ACOD1 or glutamine metabolism reduces pathogenic ZFTA-RELA levels and is potently therapeutic in multiple in vivo models. Mechanistically, ZFTA-RELA epigenetically suppresses PTEN expression to upregulate PI3K-mTOR signalling, a known driver of glutaminolysis. Finally, suppression of ACOD1 or a combination of glutamine antagonism with PI3K-mTOR inhibition abrogates spinal metastasis. Our data demonstrate that ZFTA-RELA⁺ ependymomas subvert a macrophage-like itaconate metabolic pathway to maintain expression of the ZFTA-RELA driver, which implicates itaconate as a candidate oncometabolite. Taken together, our results position itaconate upregulation as a previously unappreciated driver of ZFTA-RELA⁺ ependymomas. Our work has implications for future drug development to reduce pathogenic ZFTA-RELA expression for this brain tumour, and will advance our understanding of oncometabolites as a new class of therapeutic dependencies in cancers.