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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE204941 | GEO | 2022/12/01

REPOSITORIES: GEO

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

Project description:Mutations in IDH1, IDH2, and TET2 are recurrently observed in myeloid neoplasms and may influence prognosis. IDH1 and IDH2 encode isocitrate dehydrogenase isoforms, which normally catalyze the conversion of isocitrate to α-ketoglutarate (α-KG). Oncogenic IDH1/2 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 TET methylcytosine dioxygenases. Given their mutual exclusivity in myeloid neoplasms, IDH1, IDH2, and TET2 mutations are thought to converge on a common oncogenic mechanism. Contrary to this expectation, we observed that they have non-overlapping, 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 dysregulation in Idh2R172K cells 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 in myeloid neoplasms.

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

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DNMT3A and TET2 Mutations Increase Hematopoietic Stem Cell Fitness Through Distinct Mechanisms

Project description:Epigenetic modifying enzymes DNMT3A and TET2 are recurrently mutated in hematological disorders despite possessing opposing biochemical functions in the DNA methylation processes. Using conditional ablation, we show these contrasting genotypes result in different functional effects in hematopoietic stem cells (HSCs). Loss of Dnmt3a bestows enhanced self-renewal on HSCs in serial, competitive repopulation assays while Tet2 loss functionally depletes HSCs after a tertiary transplant despite an initial competitive advantage. Moreover, loss of Tet2 sensitizes HSCs to the addition of a common leukemic driver mutation Flt3-ITD. Tet2-null mice experience a 5-fold decrease in median survival time when combined with Flt3-ITD while that of Dnmt3a-null mice decreases 1.5-fold. Molecular characterization of transcriptomes and chromatin accessibility reflects the functional differences between the genotypes as Dnmt3a-null cells reside in a more stem cell-like state while Tet2 loss leads to functional attrition of down-stream progenitors. These data further prove that DNMT3A and TET2 mutations lead HSCs down different molecular and functional pathways despite similar disease destinations.

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Distinct Brca1 Mutations Differentially Reduce Hematopoietic Stem Cell Function.

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