Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE189502 | GEO | 2022/05/11

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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

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

| PRJNA783288 | ENA

Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Project description:Mutations in SET binding protein 1 (SETBP1) are associated with poor outcomes in myeloid leukemias. In the Ras-driven leukemia, juvenile myelomonocytic leukemia, SETBP1 mutations are enriched in relapsed disease. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways.

2021-05-18 | GSE158379 | GEO

Transcriptional regulation by SETBP1 and SETBP1(D/N) in mouse hematopoietic stem and progenitor cells

Project description:Global gene expression changes induced by Setbp1 and Setbp1(D/N) in purified mouse hematopoietic stem and progenitor cells were characterized by RNA-seq analysis; ChIP-seq studies to identify cooperation between SETBP1/SETBP1(D/N) and MLL1 in regulating gene transcription in hematopoietic stem and progenitor cells.

2021-12-17 | GSE167301 | GEO

CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers (Microarray)

Project description:Acute Myeloid Leukemia (AML) develops due to the acquisition of mutations from multiple functional classes. Here, we demonstrate that activating mutations in the granulocyte colony stimulating factor receptor (CSF3R), cooperate with loss of function mutations in the transcription factor CEBPA to promote acute leukemia development. Terminal myeloid differentiation in response to granulocyte colony-stimulating factor signaling requires wild type CEBPA and is blocked by mutations in CEBPA. Inhibition of the histone demethylase LSD1, restores differentiation and in combination with JAK/STAT blockade, produces significant disease response in vivo. Mutant CEBPA blocks myeloid differentiation by preventing the activation of differentiation-associated enhancers. As enhancer activation precedes promoter activation, CEBPA mutations must occur prior to CSF3R mutations to effectively block differentiation and promote leukemia formation in vivo. This study demonstrates that order-dependent oncogene interaction is a fundamental process in AML. Dissecting this process is critical for understanding disease evolution to enable the development of effective therapeutics.

2019-12-02 | GSE122161 | GEO

CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers (ChIP-seq)

2019-12-02 | GSE122162 | GEO

CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers (RNA-seq - orders)

2019-12-02 | GSE122163 | GEO

CEBPA Dysfunction Intiates CSF3R Mutant Acute Myeloid Leukemia Through Disruption of Myeloid Lineage Enhancers (RNA-seq - simultaneous)

2019-12-02 | GSE122164 | GEO

CSF3R T618I collaborates with RUNX1-RUNX1T1 to expand hematopoietic progenitors and sensitizes to GLI-inhibition

Project description:Activating CSF3R mutations are recurrent in AML with t(8;21) translocation. However, the nature of oncogenic collaboration between alterations of CSF3R and the t(8;21) associated RUNX1-RUNX1T1 fusion remains unclear. In CD34+ hematopoietic stem and progenitor cells from healthy donors, double oncogene expression led to a clonal advantage, increased self-renewal potential, as well as blast-like morphology and distinct immunophenotype. Gene expression profiling revealed hedgehog-signaling as a potential mechanism, with upregulation of GLI2 constituting a putative pharmacological target. Both primary hematopoietic cells and the t(8;21) positive AML cell line SKNO-1 showed increased sensitivity to the GLI-inhibitor GANT61 when expressing CSF3R T618I. Our findings suggest that during leukemogenesis the RUNX1-RUNXT1 fusion and CSF3R mutation act in a synergistic manner to alter hedgehog signaling which can be exploited therapeutically.

2023-10-18 | GSE230755 | GEO

SETBP1-WT and SETBP1-G870S transcriptional profiles [RNA-Seq]

Project description:RNA-Seq experiments on SETBP1-G870S and Empty cells was performed in order to assess if the presence of mutated SETBP1 may induce differential RNA expression.

2017-09-01 | GSE86333 | GEO

A novel germline variant in CSF3R highlights the potent oncogenic effects of loss of N-glycosylation and its implication for therapeutic intervention

Project description:Mutations in the colony stimulating factor 3 receptor (CSF3R) have been identified in the vast majority of patients with chronic neutrophilic leukemia and are present in other kinds of leukemia, such as AML. Herein, we study the function of novel germline variants in CSF3R at amino acid N610. These N610 substitutions are potently oncogenic and activate the receptor independently of its ligand, GCSF. These mutations activate the JAK-STAT signaling pathway and confer sensitivity to JAK inhibitors. The N610 residue is part of a consensus N-linked glycosylation motif in the receptor, usually linked to complex glycans, as shown by detailed mass spectrometry analysis. Further analysis demonstrates that N610 is the primary site of sialylation of the receptor. This study demonstrates that membrane-proximal N-linked glycosylation is critical for maintaining the ligand dependence of the receptor. Mutation of the N610 site prevents membrane proximal N-glycosylation of CSF3R, which then drives ligand-independent neutrophil expansion. Kinase inhibitors block growth of cells with an N610 mutation. This study expands the repertoire of oncogenic mutations in CSF3R that are therapeutically targetable and provides insight into the function of glycans in receptor regulation.

2018-11-06 | PXD011118 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data