TET-dioxygenase deficiency in oncogenesis and its targeting for tumor-selective therapeutics.

TET2 is one of the most frequently mutated genes in myeloid neoplasms. TET2 loss-of-function perturbs myeloid differentiation and causes clonal expansion. Despite extensive knowledge regarding biochemical mechanisms underlying distorted myeloid differentiation, targeted therapies are lagging. Here we review known biochemical mechanisms and candidate therapies that emerge from this. Specifically, we discuss the potential utility of vitamin C to compensate for TET-dioxygenase deficiency, to thereby restore the biochemical function. An alternative approach exploits the TET-deficient state for synthetic lethality, exploiting the fact that a minimum level of TET-dioxygenase activity is required for cell survival, rendering TET2-mutant malignant cells selectively vulnerable to inhibitors of TET-function.