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TET2 Deficiency Increases the Competitive Advantage of Hematopoietic Stem Cells through Upregulation of Thrombopoietin Receptor Signaling

ABSTRACT: TET2 Deficiency Increases the Competitive Advantage of Hematopoietic Stem Cells through Upregulation of Thrombopoietin Receptor Signaling

PROVIDER: PRJNA1100587 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28700839_1.fastq.gz	Fastqsanger.gz
	SRR28700839_2.fastq.gz	Fastqsanger.gz
	SRR28700840.fastq.gz	Fastqsanger.gz
	SRR28700840_1.fastq.gz	Fastqsanger.gz
	SRR28700840_2.fastq.gz	Fastqsanger.gz

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TET2 Deficiency Increases the Competitive Advantage of Hematopoietic Stem Cells through Upregulation of Thrombopoietin Receptor Signaling

Project description:Ten-Eleven Translocation-2 (TET2) mutations drive the expansion of mutant hematopoietic stem cells (HSCs) in clonal hematopoiesis (CH). However, the precise mechanisms by which TET2 mutations confer a competitive advantage to HSCs remain unclear. Here, through an epigenetic drug screen, we discovered that inhibition of disruptor of telomeric silencing 1-like (DOT1L), a H3K79 methyltransferase, selectively reduced the fitness of Tet2 knockout (Tet2KO) hematopoietic stem and progenitor cells (HSPCs). Mechanistically, we found that TET2 deficiency increased H3K79 dimethylation and expression of Mpl, which encodes the thrombopoietin receptor (TPO-R). Correspondingly, TET2 deficiency was associated with a higher proportion of primitive Mpl-expressing (Mpl+) cells in the HSC compartment. Importantly, inhibition of Mpl expression or the signaling downstream of TPO-R was sufficient to reduce the competitive advantage of murine and human TET2-deficient HSPCs. Our findings demonstrate a critical role for aberrant TPO-R signaling in TET2 mutation-driven CH and uncover potential therapeutic strategies against this condition.

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TET2 deficiency increases the competitive advantage of hematopoietic stem and progenitor cells through upregulation of thrombopoietin receptor signaling.

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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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Project description:The expansion of hematopoietic stem cell clones and their immune progeny carrying somatic mutations is defined as clonal hematopoiesis (CH) and its prevalence increases with age. Individuals with CH are at higher risk of developing hematological malignancies as well as other pathologies, such as cardiovascular or inflammatory pulmonary diseases. Understanding the environmental conditions that favor mutant clones and the CH-immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. In this work, we characterized how mutations in TET2, increase the competitive advantage of human HSCs upon environmental stress conditions and simultaneously shape the immune response of their myeloid progeny. Employing a humanized mouse model, we unravel a cell-specific impact of TET2 mutations on HSCs and their myeloid progeny to inflammatory stress. In such environments, TET2Mut HSCs have a mitigated transcriptional upregulation of inflammatory pathways, and by contrast, TET2Mut myeloid cells have an exacerbated inflammatory response. A distinct monocyte-macrophage trajectory derived from TET2Mut HSCs contributes to pathological inflammation. These findings provide evidence at the human cell level and reconcile the notion that TET2-derived CH is associated with both increased stemness in the HSC compartment and inflammation elicited by the myeloid progeny.

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Project description:The expansion of HSC clones and their immune progeny carrying somatic mutations is defined as clonal hematopoiesis (CH) with its prevalence increasing with age. Individuals with CH are at higher risk of developing hematological malignancies but also other pathologies, such as cardiovascular or inflammatory pulmonary diseases. Understanding which environmental conditions favor mutant clones and the CH-immune system response to such environments is key to designing therapeutic strategies to stall the expansion of mutant clones and the development of CH-associated pathologies. In this work, we characterized how mutations in TET2, one of the most frequent in CH, increase the competitive advantage of human HSCs upon environmental stress conditions and at the same time shape the immune response of their myeloid progeny. Employing a humanized mouse model, we show that environmental conditions that drive emergency myelopoiesis promote human TET2-derived CH. We unravel an opposite and cell-specific impact of TET2 mutations on HSCs and their myeloid progeny to inflammatory stress. In such environments, TET2Mut HSCs have a mitigated transcriptional upregulation of inflammatory pathways, and by contrast, TET2Mut myeloid cells have an exacerbated inflammatory response. A distinct monocyte-macrophage trajectory derived from TET2Mut HSCs contributes to pathological inflammation. These findings provide evidence at the human cell level and reconcile the notion that TET2-derived CH is associated with both increased stemness at the HSC compartment and promoted inflammatory environments from the myeloid progeny.

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