Significance Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy in need of novel targeted therapies to prevent relapse and lessen treatment toxicity. We reveal frequent (∼88%) transcriptional silencing or repression of the tumor suppressor TET2 in T-ALL. We show that loss of TET2 in T-ALL is correlated with hypermethylation of the TET2 promoter and that TET2 expression can be rescued by treatment with the DNA demethylating agent, 5-azacytidine (5-aza). We further reveal that the TET2 cofactor vitamin C exerts a strong synergistic effect on global transcriptional changes when added to 5-aza treatment. Importantly, 5-aza treatment results in increased cell death, specifically in T-ALL cells lacking TET2. Thus, we clearly identify 5-aza as a potentially targeted therapy for TET2 -silenced T-ALL.