Tet2 and Tet3 functionally overlap in vitamin C-induced epigenomic alterations in acute myeloid leukemia

Heterozygous mutations that impair the demethylase activity of the ten eleven translocation (TET) enzyme family are frequent events in de novo acute myeloid leukemia (AML). Although both TET2 and TET3 are highly expressed in AML blasts and murine leukemic models, only TET2 is mutated in AML patients, suggesting a divergent oncogenic relevance. To define the individual functions of TET2 and TET3, we inactivated both genes individually and in combination in a HoxA9/IDH1R132H murine AML model and analyzed the resulting transcriptional and epigenetic states in the presence and absence of the TET co-factor vitamin C. Despite their distinct DNA-binding characteristics, we found that Tet2- and Tet3- regulated enhancer:gene networks largely overlap and that they elicit similar cytomorphological changes when perturbed. Overall, our findings suggest that despite their divergent oncogenic relevancy, Tet2 and Tet3 act on a common myeloid differentiation pathway that can independently be activated by either Tet2 or Tet3.