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PU.1-dependent enhancer inhibition separates Tet2 deficient clonal hematopoiesis from malignant transformation

ABSTRACT: PU.1-dependent enhancer inhibition separates Tet2 deficient clonal hematopoiesis from malignant transformation

PROVIDER: PRJNA789544 | ENA |

REPOSITORIES: ENA

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PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (oxBS-Seq)

Project description:Hematopoietic stem cells sustain life-long blood production. While they are the known cellular origin of aging-associated myeloid malignancies, such as acute myeloid leukemia (AML), mechanisms driving their malignant transformation have remained elusive. Epigenetic dysregulation following acquired loss-of-function mutations of DNA methyl-cytosine dioxygenase Ten-Eleven Translocation-2 (TET2) occurs frequently in the elderly leading to cytosine hypermethylation in and around DNA binding sites of master transcription factors, including PU.1. Here we show that Tet2 deficient hematopoietic stem and progenitor cells (HSPC) undergo malignant transformation upon compromised PU.1 gene regulation. Leukemic stem and progenitor cells show hypermethylation at PU.1 binding sites and fail to activate PU.1-depenent myeloid enhancers, and are hallmarked by a defined signature of impaired genes shared with human AML. Our study demonstrates that Tet2 and PU.1 cooperate in suppressing leukemogenesis in HSPC and establishes a methylation sensitive PU.1-dependent gene network as a unifying feature in acute myeloid leukemia.

2022-07-31 | GSE194170 | GEO

PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)

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PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (RNA-Seq)

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PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)

Project description:PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (ATAC-Seq)

| PRJNA789545 | ENA

PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (oxBS-Seq)

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PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (RNA-Seq)

Project description:PU.1-dependent enhancer inhibition separates clonal hematopoiesis from malignant transformation (RNA-Seq)

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PU.1-dependent enhancer inhibition separates Tet2 deficient clonal hematopoiesis from malignant transformation

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-07-31 | GSE191053 | GEO

Tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction

Project description:Clonal hematopoiesis of indeterminate potential is prevalent in elderly individuals and associated with increased risks of all-cause mortality and cardiovascular disease. However, mouse models to study the dynamics of clonal hematopoiesis and its consequences on the cardiovascular system under homeostatic conditions are lacking. We used a model of clonal hematopoiesis using adoptive transfer of unfractionated ten-eleven translocation 2-mutant (Tet2-mutant) bone marrow cells into nonirradiated mice. Consistent with age-related clonal hematopoiesis observed in humans, these mice displayed a progressive expansion of Tet2-deficient cells in multiple hematopoietic stem and progenitor cell fractions and blood cell lineages. The expansion of the Tet2-mutant fraction was also observed in bone marrow-derived CCR+ myeloid cell populations within the heart, but there was a negligible impact on the yolk sac-derived CCR2- cardiac resident macrophage population. Transcriptome profiling revealed an enhanced inflammatory signature in the donor-derived macrophages isolated from the heart. Mice receiving Tet2-deficient bone marrow cells spontaneously developed age-related cardiac dysfunction characterized by greater hypertrophy and fibrosis. Altogether, we show that Tet2- mediated hematopoiesis contributes to cardiac dysfunction in a nonconditioned setting that faithfully models the human clonal hematopoiesis in unperturbed bone marrow. Our data support clinical findings that clonal hematopoiesis per se may contribute to diminished health span.

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Identify the key signaling pathway involved in the Tet2 deficiency-induced clonal hematopoiesis

Project description:To investigate the signaling pathway required for the Tet2 mutant associated clonal hematopoiesis, we identified the activated signaling pathway in Tet2-deficient hematopoietic stem/progenitor cells compared to WT cells and using transgentic mouse model to validate our findings. In short, the cGAS-STING pathway is activated in Tet2-deficient HSPCs and promotes the development of CH associated with Tet2 deficiency.

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Project description:TET2-mutant clonal hematopoiesis and risk of gout

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