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Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells (BS-seq)

ABSTRACT: Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells (BS-seq)

PROVIDER: PRJNA842748 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19422800_1.fastq.gz	Fastqsanger.gz
	SRR19422800_2.fastq.gz	Fastqsanger.gz
	SRR19422801_1.fastq.gz	Fastqsanger.gz
	SRR19422801_2.fastq.gz	Fastqsanger.gz
	SRR19422802_1.fastq.gz	Fastqsanger.gz

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Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells (BS-seq)

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

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Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells (RNA-Seq)

Project description:Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells (RNA-Seq)

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Project description:Distinct and opposite effects of leukemogenic Idh and Tet2 mutations in hematopoietic stem and progenitor cells (ATAC-Seq)

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Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation

Project description:Cancer-associated IDH mutations are characterized by neomorphic enzyme activity and resultant 2 hydroxyglutarate (2HG) production. Mutational and epigenetic profiling of a large AML patient cohort revealed that IDH1/2-mutant AMLs display global DNA hypermethylation and a specific hypermethylation signature. Furthermore, expression of 2HG-producing IDH alleles in cells rapidly induced global DNA hypermethylation. In the AML cohort, IDH1/2 mutations were mutually exclusive with mutations in the α-ketoglutarate-dependent enzyme TET2, and TET2 loss-of function mutations associated with similar epigenetic defects as IDH1/2 mutants. Consistent with these genetic and epigenetic data, expression of IDH mutants impaired TET2 catalytic function in cells. Finally, either expression of mutant IDH1/2 or Tet2 depletion impaired hematopoietic differentiation and increased stem cell marker expression, suggesting a shared pro-leukemogenic effect. DNA methylation and gene expression profiling in IDH1/2 mutant vs. IDH1/2 wild-type AML

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Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation

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