Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells

Mutations in IDH1, IDH2 , and TET2 are recurrently observed in myeloid neoplasms. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to & alpha;-ketoglutarate (& alpha;-KG). Oncogenic IDH1/2 mutations confer neomorphic activity, leading to the production of D-2-hydroxyglutarate (D-2-HG), a potent inhibitor of & alpha;-KG-dependent enzymes which include the TET methylcyto-sine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2 , and TET2 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 Idh2R172K and Tet2 loss-of-function have divergent consequences on the expression and activity of key hematopoietic and leukemogenic regulators. Notably, chromatin accessibility and transcriptional deregu-lation in Idh2R172Kcells were partially disconnected from DNA methylation alterations. These results highlight unanticipated divergent effects of IDH1/2 and TET2 mutations, providing support for the optimization of genotype-specific therapies.SignificanceIn myeloid neoplasms, treatment outcome is associated with the presence of specific combinations of driver mutations. Delineating their molecular effects is important to understand the basis of disease heterogeneity and to help design better therapies. We discovered that two mutually exclusive leukemogenic mutations, Idh2R172Kand Tet2 loss-of -function, unexpectedly cause opposite molecular alterations in hematopoietic stem and progenitor cells. These results could pave the way for the development of more effective and patient-specific treatments.