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Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors

ABSTRACT: Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors

PROVIDER: PRJNA758993 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15672700_1.fastq.gz	Fastqsanger.gz
	SRR15672700_2.fastq.gz	Fastqsanger.gz
	SRR15672701_1.fastq.gz	Fastqsanger.gz
	SRR15672701_2.fastq.gz	Fastqsanger.gz
	SRR15672702_1.fastq.gz	Fastqsanger.gz

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Similar Datasets

Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors

Project description:Germline mutations in ETV6 are associated with a syndrome of thrombocytopenia and leukemia predisposition, and ETV6 is among the most commonly mutated genes in leukemias, especially childhood B cell acute lymphoblastic leukemia. However, the mechanisms underlying disease due to ETV6 dysfunction are poorly understood. In order to address these gaps in knowledge, using CRISPR/Cas9, we developed a mouse model of the most common recurrent, disease-causing germline mutation in ETV6, which recapitulates aspects of human disease. We found defects in hematopoiesis, primarily related to abnormalities of the multipotent progenitor population 4 (MPP4) subset of hematopoietic progenitor cells and evidence of sterile inflammation. Expression of ETV6 in Ba/F3 cells altered the expression of several cytokines, some of which were also detected at higher levels in the bone marrow of the mice with Etv6 mutation. Among these, IL-18 and IL-13 abrogated B cell development of sorted MPP4 cells, but not common lymphoid progenitors, suggesting that inflammation contributes to abnormal hematopoiesis by impairing lymphoid development. These data, along with that from humans, support a model in which ETV6 dysfunction promotes inflammation, which adversely affects thrombopoiesis and promotes leukemogenesis.

2022-06-30 | GSE183064 | GEO

Germline ETV6 mutation promotes inflammation and disrupts lymphoid development of early hematopoietic progenitors.

Project description:Germline mutations in ETV6 are associated with a syndrome of thrombocytopenia and leukemia predisposition, and ETV6 is among the most commonly mutated genes in leukemias, especially childhood B-cell acute lymphoblastic leukemia. However, the mechanisms underlying disease caused by ETV6 dysfunction are poorly understood. To address these gaps in knowledge, using CRISPR/Cas9, we developed a mouse model of the most common recurrent, disease-causing germline mutation in ETV6. We found defects in hematopoiesis related primarily to abnormalities of the multipotent progenitor population 4 (MPP4) subset of hematopoietic progenitor cells and evidence of sterile inflammation. Expression of ETV6 in Ba/F3 cells altered the expression of several cytokines, some of which were also detected at higher levels in the bone marrow of the mice with Etv6 mutation. Among these, interleukin-18 and interleukin-13 abrogated B-cell development of sorted MPP4 cells, but not common lymphoid progenitors, suggesting that inflammation contributes to abnormal hematopoiesis by impairing lymphoid development. These data, along with those from humans, support a model in which ETV6 dysfunction promotes inflammation, which adversely affects thrombopoiesis and promotes leukemogenesis.

| S-EPMC9885892 | biostudies-literature

A germline ETV6 mutation disrupts hematopoiesis via de novo creation of a nuclear export signal

Project description:Germline mutations in the transcriptional regulator ETV6 are a root cause of familial inherited thrombocytopenia and predispose carriers to myelodysplastic syndromes and acute leukemias. Here, we report that the ETV6 P214L mutation creates an XPO1-dependent nuclear export signal to cause protein mislocalization. Strategies to disrupt XPO1 nuclear export activity fully restore ETV6 P214L protein nuclear localization and transcription regulation activity, establishing XPO1-dependent mislocalization as a critical mechanism underscoring ETV6 P214L dysfunction. Mechanistic insight inspired the design of ‘humanized’ ETV6 mice in which the germline P214L mutation is sufficient to elicit severe defects in thrombopoiesis and hematopoietic stem cell maintenance and survival in animals. These studies define a unique mechanism by which the ETV6 P214L mutation exerts a dominant negative effect on protein function and reveal critical mutation-dependent disruptions to hematopoiesis that underlie disease phenotypes.

2025-04-11 | GSE288171 | GEO

A germline ETV6 mutation disrupts hematopoiesis via de novo creation of a nuclear export signal

2025-04-23 | GSE287784 | GEO

A germline ETV6 mutation disrupts hematopoiesis via de novo creation of a nuclear export signal

Project description:A germline ETV6 mutation disrupts hematopoiesis via de novo creation of a nuclear export signal

| PRJNA1216382 | ENA

A germline ETV6 mutation disrupts hematopoiesis via de novo creation of a nuclear export signal

Project description:A germline ETV6 mutation disrupts hematopoiesis via de novo creation of a nuclear export signal

| PRJNA1214692 | ENA

Identification of ETV6 bound protein by affinity purification of ETV6-HA fusion protein in REH cells

Project description:To determine the protein partners of ETV6, we expressed ETV6 and HA-tagged ETV6 in Reh pre-B leukemic cells. Anti-HA magnetic beads were used for affinity purification of ETV6-HA (and ETV6 control) from the nuclear and cytoplasmic fraction. Following purification on-beads digest and LC-MS/MS experiments were performed at the Proteomics platform of the CHU de Quebec Research Center, Quebec, Canada.

2022-01-26 | PXD031001 | Pride

Insights into inherited thrombocytopenia resulting from mono-allelic germline mutations in ETV6 or RUNX1 using a human pluripotent stem cell model

Project description:Inherited thrombocytopenia results in low platelet counts and increased bleeding. Subsets of these patients have monoallelic germline mutations in ETV6 or RUNX1 and a heightened risk of developing hematologic malignancies. Utilizing CRISPR/Cas9, we compared the in vitro phenotype of hematopoietic progenitor cells and megakaryocytes derived from induced pluripotent stem cell (iPSC) lines harboring mutations in either ETV6 or RUNX1. Both mutant lines display phenotypes consistent with a platelet-bleeding disorder. Surprisingly, these cellular phenotypes were largely distinct. The ETV6-mutant iPSCs yield more hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are immature and less responsive to agonist stimulation. On the contrary, RUNX1-mutant iPSCs yield fewer hematopoietic progenitor cells and megakaryocytes, but the megakaryocytes are more responsive to agonist stimulation. However, both mutant iPSC lines display defects in proplatelet formation. Our work highlights that while patients harboring germline ETV6 or RUNX1 mutations have similar clinical phenotypes, the molecular mechanisms may be distinct.

2021-03-06 | GSE168326 | GEO

Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

2020-10-30 | GSE148189 | GEO

Single cell characterization of arrested B-lymphoid differentiation and leukemic cell states in ETV6-RUNX1-positive pediatric leukemia

Project description:Arrested bone marrow (BM) lymphoid cell differentiation underlies the emergence of the most common childhood cancer, acute lymphoblastic leukemia (ALL). Recurrent genetic lesions often directly involve transcription factors (TFs), such as ETV6 and RUNX1 found in the most common ALL translocation. Here, we studied differential gene expression in ETV6-RUNX1 primary ALL samples and the REH cell line using single cell RNA-seq (scRNA-seq). Submitter declares that the raw data will be deposited in EGA due to patient privacy concerns. The raw data can be accessed at https://www.ebi.ac.uk/ega/studies/EGAS00001004374

2020-10-30 | GSE148218 | GEO

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