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.
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