Molecular Cooperativity of Dnmt3a and Npm1 Mutations in Transformation from Clonal Hematopoiesis to Myeloid Malignancy
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA797385 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17621964_1.fastq.gz | Fastqsanger.gz | |||
| SRR17621964_2.fastq.gz | Fastqsanger.gz | |||
| SRR17621965_1.fastq.gz | Fastqsanger.gz | |||
| SRR17621965_2.fastq.gz | Fastqsanger.gz | |||
| SRR17621966_1.fastq.gz | Fastqsanger.gz |
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Project description:Driver somatic mutations in adult acute myeloid leukemia (AML) may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we utilize mice with inducible mutant alleles common in CH (DNMT3AR882; mouse Dnmt3aR878H/+) and AML (NPM1c; mouse Npm1cA/+). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced expression of cytokine and pro-inflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. These Dnmt3aR878H/+ HSCs are transformed by activation of Npm1cA/+, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA/+ acutely increased accessibility of a distinct set of promoters in cooperation with Dnmt3aR878H/+ than it did as a single mutation. These promoters were enriched for pro-inflammatory response signatures, p53 pathway, DNA repair and targets of transcription factors implicated in AML, including Hmgb1 and Pax4. These results suggest cooperativity between pre-existing Dnmt3a mutation and Npm1 mutation at the chromatin level, where specific loci altered in accessibility by the Npm1 mutation are dependent on Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention of the transformation from CH to AML.
2022-01-21 | GSE193720 | GEO
Project description:Adult de novo acute myeloid leukemia (AML) is a hematologic malignancy with poor prognosis, commonly driven by mutations in genes including the DNA methyltransferase DNMT3A and nucleophosmin NPM1. We previously generated sequentially inducible mouse models of these mutations and observed transformation from clonal hematopoiesis (CH) to myeloproliferative disorder to AML. In transformed AML, leukemia-propagating cells have a myeloid-restricted progenitor cell phenotype (c-Kit+). Here, to identify mechanisms that sustain tumorigenesis, we performed single-cell RNA-seq of c-Kit+ cells from four primary Dnmt3a;Npm1-mutant AML samples. The most primitive subset of c-Kit+ cells, a multipotent progenitor population Multi-Lin-2, had increased expression of the antioxidant and heavy metal chelator metallothionein 1 (Mt1) in all AML samples. Cas9-mediated Mt1 knockout in primary Dnmt3a;Npm1-mutant AML resulted in reduced cell cycling and proliferation and increased pyroptosis in vitro and increased overall survival following transplant into congenic recipient mice.
2024-03-26 | GSE262264 | GEO
Project description:In adult acute myeloid leukemia (AML), the acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced cytokine expression and proinflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA, in cooperation with Dnmt3aR878H, acutely increased the accessibility of a distinct set of promoters in HSCs compared with MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors, including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between preexisting Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention in the transformation from CH to AML.
| S-EPMC9631557 | biostudies-literature
Project description:Driver somatic mutations in adult acute myeloid leukemia (AML) are often preceded by a benign or premalignant state termed clonal hematopoiesis (CH) for which the greatest risk factor is aging. To risk-stratify aged individuals and develop therapies to prevent AML, we need to understand the variables that promote transformation from CH to AML. Using our orthogonally inducible Dnmt3aR878H;Npm1cA-mutant model of progression from CH to myeloid malignancy, we find that in young mice, Dnmt3a mutation buffers against myeloid differentiation, proliferation, acquisition of cooperating mutations and transformation induced by stress, inflammation, and the oncogenic Npm1 mutation. However, when Dnmt3a;Npm1-mutant hematopoietic stem cells (HSCs) are transplanted into naturally aged recipient mice, they gain myeloid-biased differentiation capacity and have an accelerated transformation to AML. These results support the hypothesis that alterations in the aged microenvironment drive risk of AML in individuals with CH and help to explain why this Dnmt3a mutation is exceedingly rare in pediatric leukemias.
2021-07-15 | GSE180116 | GEO
Project description:Somatic mutations in DNA Methyltransferase 3A (DNMT3A) with a hotspot in exon 23 at Arginine 882 (DNMT3AR882mut) are the most frequent single mutations in clonal hematopoiesis. Here we analyze the expression of genes and endogenous retrovirus (ERV) sequences in a murine model carrying human DNMT3A-R882H mutation in one allele of the endogenous DNMT3A with respect to normal condition and azacitidine treatment.
2021-01-26 | GSE146907 | GEO
Project description:Hematopoietic mutations in epigenetic regulators like DNA methyltransferase 3 alpha (DNMT3A) drive clonal hematopoiesis of indeterminate potential (CHIP) and are associated with adverse prognosis in patients with heart failure (HF). The interactions between CHIP-mutated cells and other cardiac cell types remain unknown. Here, we identify fibroblasts as potential interaction partners of CHIP-mutated monocytes using combined transcriptomic data from peripheral blood mononuclear cells of HF patients with and without CHIP and cardiac tissue. We demonstrate that DNMT3A inactivation augments macrophage-to-cardiac fibroblasts interactions and induces cardiac fibrosis in mice and humans. Mechanistically, DNMT3A inactivation increases the release of heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) to activate cardiac fibroblasts. These findings not only identify a novel pathway of DNMT3A CHIP-driver mutation-induced instigation and progression of HF, but may also provide a rationale for the development of new anti-fibrotic strategies.
2023-10-20 | E-MTAB-13384 | biostudies-arrayexpress
Project description:Accumulation of fatty bone marrow (FBM) is one of the key age related changes possibly influencing the blood system. While a link between obesity and cancer evolution has been reported it remains unknown whether FBM can modify the evolution of the early stages of leukemia and clonal hematopoiesis (CH). To address this question, we established different FBM mouse models in immunodeficient mice in whom we can study both mouse and human cells. We focused our studies on two FBM models: 1) after sublethal irradiation; 2) after castration; and in both we used an adipogenesis inhibitor as a control (PPARγ inhibitor). We transplanted both human and mice hematopoietic stem cells (HSCs) carrying DNMT3A mutations into immunodeficient mice with FBM. A significant increase in self-renewal was found when DNMT3AMut-HSCs were exposed to FBM. To better understand the mechanisms of the FBM-CH interaction, we performed single cell RNA-sequencing on HSPCs after FBM exposure in vivo. A 6-10 fold increase in DNMT3AMut-HSCs was observed under FBM conditions in comparison to normal bone marrow. Mutated HSCs from mice exposed to FBM exhibited an activated inflammatory signaling (IL-6 and IFNγ). Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrated increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduced the selective advantage of mice derived DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 receptor.
2023-02-19 | E-MTAB-12614 | biostudies-arrayexpress
Project description:Accumulation of fatty bone marrow (FBM) is one of the key age related changes possibly influencing the blood system. While a link between obesity and cancer evolution has been reported it remains unknown whether FBM can modify the evolution of the early stages of leukemia and clonal hematopoiesis (CH). To address this question, we established different FBM mouse models in immunodeficient mice in whom we can study both mouse and human cells. We focused our studies on two FBM models: 1) after sublethal irradiation; 2) after castration; and in both we used an adipogenesis inhibitor as a control (PPARγ inhibitor). We transplanted both human and mice hematopoietic stem cells (HSCs) carrying DNMT3A mutations into immunodeficient mice with FBM. A significant increase in self-renewal was found when DNMT3AMut-HSCs were exposed to FBM. To better understand the mechanisms of the FBM-CH interaction, we performed single cell RNA-sequencing on HSPCs after FBM exposure in vivo. A 6-10 fold increase in DNMT3AMut-HSCs was observed under FBM conditions in comparison to normal bone marrow. Mutated HSCs from mice exposed to FBM exhibited an activated inflammatory signaling (IL-6 and IFNγ). Cytokine analysis of BM fluid and BM derived adipocytes grown in vitro demonstrated increased IL-6 levels under FBM conditions. Anti-IL-6 neutralizing antibodies significantly reduced the selective advantage of mice derived DNMT3AMut-HSCs exposed to FBM. Overall, paracrine FBM inflammatory signals promote DNMT3A-driven clonal hematopoiesis, which can be inhibited by blocking the IL-6 receptor.
2023-02-19 | E-MTAB-12613 | biostudies-arrayexpress
Project description:Inflammatory signals from fatty bone marrow support DNMT3a-driven clonal hematopoiesis (Dnmt3A KI heterozygote subset)
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Project description:Inflammatory signals from fatty bone marrow support DNMT3a-driven clonal hematopoiesis (wt/DNMT3A KI subset)
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