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Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

ABSTRACT: Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

PROVIDER: PRJNA783288 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR17028100.fastq.gz	Fastqsanger.gz
	SRR17028101.fastq.gz	Fastqsanger.gz
	SRR17028102.fastq.gz	Fastqsanger.gz
	SRR17028027.fastq.gz	Fastqsanger.gz
	SRR17028028.fastq.gz	Fastqsanger.gz

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Mutant-SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms

Project description:Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of CNL patients also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutant leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutant hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs—most strongly upregulating Myc and Myc target genes. In summary, we find that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutant CSF3R through the upregulation of Myc-associated gene expression programs.

2022-05-11 | GSE189502 | GEO

Mutated SETBP1 activates transcription of Myc programs to accelerate CSF3R-driven myeloproliferative neoplasms.

Project description:Colony stimulating factor 3 receptor (CSF3R) mutations lead to JAK pathway activation and are the molecular hallmark of chronic neutrophilic leukemia (CNL). Approximately half of patients with CNL also have mutations in SET binding protein 1 (SETBP1). In this study, we developed models of SETBP1-mutated leukemia to understand the role that SETBP1 plays in CNL. SETBP1 mutations promote self-renewal of CSF3R-mutated hematopoietic progenitors in vitro and prevent cells from undergoing terminal differentiation. In vivo, SETBP1 mutations accelerate leukemia progression, leading to the rapid development of hepatosplenomegaly and granulocytosis. Through transcriptomic and epigenomic profiling, we found that SETBP1 enhances progenitor-associated programs, most strongly upregulating Myc and Myc target genes. This upregulation of Myc can be reversed by LSD1 inhibitors. In summary, we found that SETBP1 mutations promote aggressive hematopoietic cell expansion when expressed with mutated CSF3R through the upregulation of Myc-associated gene expression programs.

| S-EPMC9373012 | biostudies-literature

Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [Cut & Tag]

Project description:Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [Cut & Tag]

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Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [ATAC-Seq]

Project description:Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [ATAC-Seq]

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Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [RNA-Seq]

Project description:Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [RNA-Seq]

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Myelodysplastic/myeloproliferative neoplasms

Project description:This SuperSeries is composed of the following subset Series: GSE21948: High Density custom Agilent 44K CGH array analysis of 7q and TET2 region in myelodysplastic/myeloproliferative neoplasms GSE21990: Affymetrix SNP 6.0 array data for myelodysplastic/myeloproliferative neoplasms Refer to individual Series

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Project description:Cardiovascular events are the leading cause of death in patients with JAK2V617F myeloproliferative neoplasms. Their mechanisms are poorly understood. To investigate the role of microvesicles in these events, we performed a proteomic analysis of microvesicles derived from red blood cells from mice with a myeloproliferative neoplasms (Jak2V617F Flex/WT ;VE-cadherin-Cre) vs. littermate controls.

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Comprehensive profiing of clinical JAK inhibitors in myeloproliferative neoplasms

Project description:Comprehensive profiing of clinical JAK inhibitors in myeloproliferative neoplasms

2023-05-24 | GSE229712 | GEO

Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [ATAC-Seq]

Project description:Mutations in the epigenetic regulator Additional Sex Combs-Like 1 (ASXL1) are frequently observed in chronic neutrophilic leukemia (CNL). This disease is classically driven by activating mutations in Colony Stimulating Factor 3 Receptor (CSF3R), which promote the overproduction of neutrophils that characterizes this disease. Despite high rates of co-occurrence, the interplay between ASXL1 and CSF3R mutations in hematopoiesis and leukemia development remains poorly understood. Here, we present a new mouse model with both Asxl1Y588X and Csf3rT621I mutations, which recapitulates features of human CNL. Csf3r-mutant mice exhibit an age-associated depletion of hematopoietic stem and progenitor cells, which is reversed by the addition of Asxl1Y588X. This combination of mutations causes an expansion of myeloid-biased stem cells. As the mice age they develop neutrophilia, but leukemia is rare, suggesting additional mutations may be required for transformation. Using models of myeloid differentiation, we find that ASXL1 truncation enhances CSF3RT618I-driven neutrophil differentiation by downregulating MYC programs and activating inflammatory pathways associated with mature myeloid cell production. Moreover, cells with both mutations had increased priming of neutrophil-associated enhancers and reduced priming of enhancers associated with monocytic differentiation. Mutant ASXL1 is known to decrease genome-wide abundance of a repressive histone mark—H2AK119ub. While we see the expected decrease in H2AK119ub in Asxl1-mutant cells, this effect is reversed when CSF3R is also mutated, suggesting a complex interplay between these mutations in regulating chromatin dynamics during hematopoiesis. Our findings highlight context-dependent effects of ASXL1 mutation in myeloid disorders and provide insights into the mechanisms underlying neutrophil differentiation in ASXL1-mutant CNL.

2025-01-22 | GSE266087 | GEO

Asxl1 mutation enhances differentiation in CSF3R-mutated myeloproliferative neoplasms [RNA-Seq]

2025-01-22 | GSE266091 | GEO