A Therapeutic Strategy for Preferential Targeting of TET2 Mutant and TET-dioxygenase Deficient Cells in Myeloid Neoplasms.

is frequently mutated in myeloid neoplasms. Genetic TET2 deficiency leads to skewed myeloid differentiation and clonal expansion, but minimal residual TET activity is critical for survival of neoplastic progenitor and stem cells. Consistent with mutual exclusivity of and neomorphic mutations, here we report that IDH1/2 mutant-derived 2-hydroxyglutarate is synthetically lethal to TET-dioxygenase deficient cells. In addition, a TET-selective small molecule inhibitor decreased cytosine hydroxymethylation and restricted clonal outgrowth of mutant, but not normal hematopoietic precursor cells and . While TET-inhibitor phenocopied somatic mutations, its pharmacologic effects on normal stem cells were, unlike mutations, reversible. Treatment with TET inhibitor suppressed the clonal evolution of mutant cells in murine models and -mutated human leukemia xenografts. These results suggest that TET inhibitors may constitute a new class of targeted agents in mutant neoplasia.