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Cell of origin epigenetic priming determines susceptibility to Tet2 oncogenic mutation [scATAC-seq]

ABSTRACT: Hematopoietic stem cell mutations can result in clonal hematopoiesis (CHIP) but the clinical outcomes are heterogeneous. The nature of the founder mutation and secondary mutations likely drive emergent neoplastic disease. We investigated how the cell state where the TET2 mutation occurs affects susceptibility to that commonly occurring CH mutation. Here, we provide evidence that risk is written in the epigenome of the cell of origin. By characterizing cell states that underlie myeloid differentiation and linking this information to an inducible system to assess myeloid progenitor clones, we provide evidence that epigenetic markers of the cell where Tet2 mutation occurs stratifies clonal behaviors. Specifically, Sox4 fosters a global cell state of high sensitization towards Tet2 KO. Using GMP and primary HSC models, we show that Sox4 promotes cell dedifferentiation, alters cell metabolism and increases the in vivo clonal output of mutant cells. Our results validate the hypothesis that epigenetic features can predispose specific clones for dominance and explain why an identical mutation can result in different outcomes.

ORGANISM(S): Mus musculus

PROVIDER: GSE227314 | GEO | 2024/03/14

REPOSITORIES: GEO

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Cell of origin epigenetic priming determines susceptibility to Tet2 oncogenic mutation [bulk ATAC-seq]

Project description:Hematopoietic stem cell mutations can result in clonal hematopoiesis (CHIP) but the clinical outcomes are heterogeneous. The nature of the founder mutation and secondary mutations likely drive emergent neoplastic disease. We investigated how the cell state where the TET2 mutation occurs affects susceptibility to that commonly occurring CH mutation. Here, we provide evidence that risk is written in the epigenome of the cell of origin. By characterizing cell states that underlie myeloid differentiation and linking this information to an inducible system to assess myeloid progenitor clones, we provide evidence that epigenetic markers of the cell where Tet2 mutation occurs stratifies clonal behaviors. Specifically, Sox4 fosters a global cell state of high sensitization towards Tet2 KO. Using GMP and primary HSC models, we show that Sox4 promotes cell dedifferentiation, alters cell metabolism and increases the in vivo clonal output of mutant cells. Our results validate the hypothesis that epigenetic features can predispose specific clones for dominance and explain why an identical mutation can result in different outcomes.

2024-03-14 | GSE247969 | GEO

Cell of origin epigenetic priming determines susceptibility to Tet2 oncogenic mutation [scRNA-seq]

2024-03-14 | GSE247968 | GEO

Cell of origin epigenetic priming determines susceptibility to Tet2 mutation

Project description:Hematopoietic stem cell (HSC) mutations can result in clonal hematopoiesis (CH) with heterogeneous clinical outcomes. Here, we investigated how the cell state preceding Tet2 mutation impacts the pre-malignant phenotype. Using an inducible system for clonal analysis of myeloid progenitors, we found that the epigenetic features of clones at similar differentiation status were highly heterogeneous and functionally responded differently to Tet2 mutation. Cell differentiation stage also influenced Tet2 mutation response indicating that the cell of origin's epigenome modulates clone-specific behaviors in CH. Molecular features associated with higher risk outcomes include Sox4 that sensitized cells to Tet2 inactivation, inducing dedifferentiation, altered metabolism and increasing the in vivo clonal output of mutant cells, as confirmed in primary GMP and HSC models. Our findings validate the hypothesis that epigenetic features can predispose specific clones for dominance, explaining why identical genetic mutations can result in different phenotypes.

1970-01-01 | MTBLS9914 | MetaboLights

Mutation Order Affects Tumor Evolution and Clinical Course of Disease

Project description:Background: Cancers result from accumulation of somatic mutations and their properties are thought to reflect the sum of these mutations. However, little is known about the consequences of altering the order of mutation acquisition. Methods: Mutation order was determined in myeloproliferative neoplasm patients by genotyping hematopoietic colonies or next generation sequencing. Stem and progenitor cells were isolated to study the effect of mutation order on mature and immature hematopoietic cells. Results: Age of presentation, acquisition of JAK2V617F homozygosity and the balance of immature progenitors were all influenced by mutation order. Compared to TET2-first patients, JAK2-first patients had an increased likelihood of presenting with polycythemia vera than essential thrombocythemia, an increased risk of thrombosis and an increased sensitivity of JAK2-mutant progenitors to ruxolitinib in vitro. In studies of single hematopoietic stem and progenitor cells (HSPCs), mutation order influenced the proliferative response to JAK2V617F and the capacity of double-mutant HSPCs to generate colony-forming cells. Moreover the HSPC compartment was dominated by TET2 single-mutant cells in TET2-first patients but by JAK2/TET2 double-mutant cells in JAK2-first patients. Prior mutation of TET2 altered the transcriptional consequences of JAK2V617F in a cell-intrinsic manner, and prevented JAK2V617F from up-regulating genes associated with proliferation. These data demonstrate that mutation order influences progenitor proliferation and terminal cell expansion, thus influencing clinical presentation, thrombosis risk and progenitor response to targeted therapy. Conclusions: The order in which JAK2 and TET2 mutations are acquired influences clinical features, stem/progenitor cell biology and clonal evolution in patients with myeloproliferative neoplasms.

2014-11-17 | E-MTAB-3086 | biostudies-arrayexpress

Affymetrix SNP6.0 microarray data - Myelodysplastic syndromes

Project description:Mutations in the TET2 gene are frequent in myeloid disease, although their biological and prognostic significance remains unclear. We analyzed 355 patients with myelodysplastic syndromes using ‘Next-Generation’ sequencing (NGS) for TET2 aberrations; 91 of whom were also subjected to SNP6 array karyotyping. Seventy-one TET2 mutations, with a relative mutation abundance (RMA) ≥10%, were identified in 39 of 320 (12%) MDS and 16 of 35 (46%) CMML patients (p<0.001). Interestingly, 4 patients had multiple mutations likely to exist as independent clones or on alternate alleles, suggestive of clonal evolution. ‘Deeper’ sequencing of 96 patient samples identified 4 additional mutations (RMA 3%-6.3%). Importantly, TET2 mutant clones were also found in T cells in addition to CD34+ and total bone-marrow cells (23.5%, 38.5% and 43% RMA respectively). Only 20% of the TET2-mutated patients showed loss of heterozygosity at the TET2 locus. There was no difference in the frequency of genome-wide aberrations, TET2 expression or the JAK2V617F 46/1 haplotype between TET2-mutated and non-mutated patients. There was no significant prognostic association between TET2 mutations and WHO subtypes, IPSS score, cytogenetic status, or transformation to AML. On multivariate analysis, age (>50yrs) was associated with a higher incidence of TET2 mutation (p=0.02). Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from bone marrow or peripheral blood samples. Copy number and acquired UPD analysis of Affymetrix SNP 6.0 arrays was performed for 91 cases with Myelodysplastic syndromes.

2010-07-30 | E-GEOD-23300 | biostudies-arrayexpress

Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia. Stolzel et al. JCI Insight. [RNA-Seq]

Project description:To investigate the impact of TET2 loss on global transcription in HEL acute myeloid leukaemia (AML) cells. HEL AML cells, which have a monoallelic TET2 mutation, were targeted by CRISPR to inactivate the remaining TET2 allele, generating isogenic cell clones with either monoallelic or biallelic TET2 mutation.

2023-03-08 | GSE218227 | GEO

Biallelic TET2 mutation sensitizes to 5’-azacitidine in acute myeloid leukemia. Stolzel et al. JCI Insight. [Illumina Infinium]

Project description:To investigate the impact of TET2 loss on global genomic methylation in HEL acute myeloid leukaemia (AML) cells. HEL AML cells, which have a monoallelic TET2 mutation, were targeted by CRISPR to inactivate the remaining TET2 allele, generating isogenic cell clones with either monoallelic or biallelic TET2 mutation.

2023-03-08 | GSE217940 | GEO

Macrophage migration inhibitory factor is overproduced through EGR1 in TET2low resting monocytes

Project description:Somatic mutation in TET2 gene is one of the most common clonal genetic events detected in age-related clonal hematopoiesis as well as in chronic myelomonocytic leukemia (CMML). In addition to being a pre-malignant state, TET2 mutated clones are associated with an increased risk of death from cardiovascular disease, which could involve cytokine/chemokine overproduction by monocytic cells. Here, we show in mice and in human cells that, in the absence of any inflammatory challenge, TET2 down-regulation promotes the production of MIF (macrophage migration inhibitory factor), a pivotal mediator of atherosclerotic lesion formation. In healthy monocytes, TET2 is recruited to MIF promoter and interacts with the transcription factor EGR1 and histone deacetylases. Disruption of these interactions as a consequence of TET2-decreased expression favors EGR1-driven transcription of MIF gene and its secretion. MIF favors monocytic differentiation of myeloid progenitors. These results designate MIF as a chronically overproduced chemokine and a potential therapeutic target in patients with clonal TET2 down-regulation in myeloid cells.

2021-11-13 | GSE188624 | GEO

Affymetrix SNP6.0 microarray data - Myelodysplastic syndromes

2010-07-30 | GSE23300 | GEO

Gene expression profile at single cell level of donor hematopoietic stem cells and multipotent progenitors 3 from bone marrow in control and Tet2 knockout mice.

Project description:HSPCs cells exhibit heterogeneous clonal expansion upon Tet2 KO. We used scRNA-seq to analyze the molecular basis for clones exhibiting high levels of expansion.

2022-12-31 | GSE212534 | GEO

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