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

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

PROVIDER: PRJNA665040 | ENA |

REPOSITORIES: ENA

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			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

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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

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. 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

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

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

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.

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SETBP1-WT and SETBP1-G870S epigenetic landscapes [ChIP-Seq]

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

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eIF4F controls ERK MAPK signaling in melanomas with BRAF and NRAS mutations

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.

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SETBP1-WT and SETBP1-G870S epigenetic landscapes

Project description:SETBP1-WT and SETBP1-G870S epigenetic landscapes

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SETBP1-WT and SETBP1-G870S DNA binding propensity [ChIP-Seq TF]

Project description:ChIP-seq against V5 has been performed in order to investigate the role of SETBP1 as a DNA binding protein

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Melanoma NRAS - Cooperative induction of apoptosis in nras mutant melanoma by inhibition of mek and rock

Project description:In the present work we propose a new therapy for NRAS mutant melanoma. Simultaneous inhibition of MEK and ROCK caused induction of BimEL , PARP, and Puma, and hence apoptosis. In vivo, MEK and ROCK inhibition suppressed growth of established tumors. Our findings warrant clinical investigation of the effectiveness of combinatorial targeting of MAPK/ERK and ROCK in NRAS mutant melanoma.

2015-03-11 | PXD000528 | Pride

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