Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 10-15% of human cancers. ALT cancers are strongly associated with inactivating mutations in ATRX; yet loss of ATRX alone is insufficient to trigger ALT, and this means additional factors are needed to turn ON ALT. We have shown that mutations of histone H3.3 (H3.3 G34R) and Krebs cycle gene Isocitrate dehydrogenase I (IDH1 R132H) are two such factors in gliomas. Both mutations inhibit H3K9/K36 KDM4B demethylase. Primary cell models inactivated for ATRX, KDM4B (by H3.3 G34R or IDH1 R132H), TERT (telomerase) and TP53 tumour suppressor develop ALT features. In addition, KDM4B overexpression disrupts ALT activity, suggesting that KDM4B inactivation is the ‘missing factor’ that acts with ATRX mutation to turn on ALT. We have found that KDM4B regulates chromatin accessibility at telomeres, with its loss of function resulting in telomeric replication stress and damage. IDH1 R132H inhibits KDM4B by producing a 2-hydroxyglutarate onco-metabolite, thus, inducing replication stress at telomeres. ATRX mutations and ALT are also found in paragangliomas and pheochromocytomas and these tumours have frequent mutations in Krebs cycle genes fumarate hydratase (FH) and succinate dehydrogenase (SDHx), leading to an accumulation of fumarate and succinate. We investigate if fumarate and succinate act as onco-metabolites that inhibit KDM4B at telomeres, and if FH and SDHx mutations also induce telomeric replication stress and promote ALT in ATRX-mutated cancers. New findings will be presented.