Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA665040 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12693651.fastq.gz | Fastqsanger.gz | |||
| SRR12693652.fastq.gz | Fastqsanger.gz | |||
| SRR12693653.fastq.gz | Fastqsanger.gz | |||
| SRR12693654.fastq.gz | Fastqsanger.gz | |||
| SRR12693655.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
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
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. While some mechanisms for SETBP1-driven oncogenesis have been established, it remains unclear how SETBP1 specifically modulates the biology of Ras-driven leukemias. In this study, we found that when co-expressed with Ras pathway mutations, SETBP1 promoted oncogenic transformation of murine bone marrow in vitro and aggressive myeloid leukemia in vivo. We demonstrate that SETBP1 enhances the NRAS gene expression signature, driving upregulation of mitogen-activated protein kinase (MAPK) signaling and downregulation of differentiation pathways. SETBP1 also enhances NRAS-driven phosphorylation of MAPK proteins. Cells expressing NRAS and SETBP1 are sensitive to inhibitors of the MAPK pathway, and treatment with the MEK inhibitor trametinib conferred a survival benefit in a mouse model of NRAS/SETBP1-mutant disease. Our data demonstrate that despite driving enhanced MAPK signaling, SETBP1-mutant cells remain susceptible to trametinib in vitro and in vivo, providing encouraging preclinical data for the use of trametinib in SETBP1-mutant disease.
| S-EPMC8595361 | biostudies-literature
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
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
Project description:The eIF4F translation initiation complex plays a critical role in melanoma resistance to clinical BRAF and MEK inhibitors. In this study, we uncover a novel function of eIF4F in the negative regulation of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway. We demonstrate that eIF4F is essential for maintaining optimal ERK signaling intensity in treatment-naïve melanoma cells harboring BRAF or NRAS mutations. Specifically, the dual-specificity phosphatase DUSP6/MKP3, which acts as a negative feedback regulator of ERK activity, requires continuous production in an eIF4F-dependent manner to limit excessive ERK signaling driven by oncogenic RAF/RAS mutations. Treatment with small molecule eIF4F inhibitors disrupts the negative feedback control of MAPK signaling, leading to ERK hyperactivation and EGR1 overexpression in melanoma cells in vitro and in vivo. Furthermore, our quantitative analyses reveal a high spare signaling capacity in the ERK pathway, suggesting that eIF4F-dependent feedback keeps the majority of ERK molecules inactive under normal conditions. Overall, our findings highlight the crucial role of eIF4F in regulating ERK signaling flux and suggest that pharmacological eIF4F inhibitors can disrupt the negative feedback control of MAPK activity in melanomas with BRAF and NRAS activating mutations.
2024-10-04 | GSE273721 | GEO
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
Project description:ChIP-Seq experiments targeting H3K4me2, H3K4me3, H3K9ac, H3K27ac, H3K36me3 histone modifications have been performed in order to assess if SETBP1 binding to gDNA was associated with chromatin remodeling and to further characterize the mechanisms responsible for SETBP1-mediated transcriptional regulation
2017-09-01 | GSE86328 | GEO
Project description:NRAS is commonly mutated in several different types of human cancer. NRAS-mutant tumors are aggressive and associated with poor outcomes. Although the development of targeted therapies as well as immune checkpoint inhibitors has led to a substantial improvement in the overall survival of patients with NRAS wild-type tumors, current therapies for NRAS-mutant cancers are limited. Here, analysis of RNA-sequencing data revealed a downregulation of the type I interferon response in NRAS-mutant tumors compared with NRAS wild-type tumors, which was associated with poor prognosis in NRAS-mutant melanoma. Knockdown of mutant NRAS, but not wild-type NRAS, enhanced the activation of cGAS-STING signaling. The formation of a trimeric complex between TBK1, STING, and IRF3, which is required for the activation and nuclear translocation, was blocked in NRAS-mutant tumor cells. Inactivation of innate immune signaling by mutant NRAS altered cytokine production, resulting in cell autonomous and non-cell autonomous signaling to prevent tumor cell death and in evasion of tumor immune surveillance. Screening of drugs for the ability to stimulate the release of CXCL10 revealed that SOS1 inhibitors reactivated cGAS-STING signaling in NRAS-mutant tumor cells. Importantly, combining SOS1 inhibitors with STING agonists maximized the activation of cGAS-STING signaling and elicited an increased antitumor immune response in vitro and in vivo. Overall, this study provides insights into the regulation of anti-tumor immunity by mutant NRAS and uncovers a potential strategy for treating NRAS-mutant cancer.
2025-05-11 | GSE290171 | GEO
Project description:SETBP1-WT and SETBP1-G870S epigenetic landscapes
| PRJNA341463 | ENA
Project description:Despite the advent of immune-oncological therapies, patients with advanced NRAS-mutant melanoma still have a significantly worse prognosis than their BRAF-mutant counterparts. This is mainly due to a high propensity for resistance to available therapies targeting the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway (MAPKi). Preclinical studies and mouse models have implicated the stress-activated MEK5/ERK5 MAPK cascade as a major resistance pathway activated by MAPKi-based targeted therapy in NRAS-mutant melanoma. Accordingly, MAPKi/ERK5i co-inhibition was capable of triggering a sustained cell cycle arrest in NRAS-mutant melanoma cells, but the key mediator(s) of its vigorous anti-proliferative effect remain elusive. Here, we further investigated the mechanism of MAPKi/ERK5i-induced cell cycle arrest in NRAS-mutant melanoma cells using both genetic methods and pharmacological inhibitors. Transcriptome analysis of human NRAS-mutant melanoma cells established that MAPKi/ERK5i-induced a near-complete shutdown of the mitotic machinery as consequence of a sustained G1 cell cycle arrest. This arrest was not only observed in diverse treatment-naïve melanoma cells but could also be induced in cells that already had developed resistance to therapeutic MEK inhibition (MEKi) and was accompanied by suppression of Cyclin D1 and E2F-mediated gene expression. Forced expression of Cyclin D1 and its effector kinase CDK4 restored cell cycle progression and mitotic gene expression in NRAS-mutant melanoma cells exposed to MEKi/ERK5i, implying Cyclin D/CDK4 activity as major target of combined MEKi/ERK5i. These findings suggest Cyclin D/CDK4 dependency as a major vulnerability of NRAS-mutant melanoma that could effectively be targeted by combined MAPKi/ERK5i.
2025-09-01 | GSE300191 | GEO