Distinct and opposite effects of leukemogenic <i>Idh</i> and <i>Tet2</i> mutations in hematopoietic stem and progenitor cells.

Abstract

Mutations in <i>IDH1,</i> <i>IDH2</i>, and <i>TET2</i> are recurrently observed in myeloid neoplasms. <i>IDH1</i> and <i>IDH2</i> encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic <i>IDH1/2</i> mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of α-KG-dependent enzymes which include the TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, <i>IDH1</i>, <i>IDH2</i>, and <i>TET2</i> mutations may converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have distinct, and even opposite, effects on hematopoietic stem and progenitor cells in genetically engineered mice. Epigenetic and single-cell transcriptomic analyses revealed that <i>Idh2^R172K</i> and <i>Tet2</i> loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregulation in <i>Idh2^R172K</i> cells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of <i>IDH1/2</i> and <i>TET2</i> mutations, providing support for the optimization of genotype-specific therapies.