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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE158379 | GEO | 2021/05/18

REPOSITORIES: GEO

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

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

| PRJNA665040 | ENA

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

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

Kinome profiling of patient JMML samples pre- and post-trametinib treatment

Project description:Juvenile myelomonocytic leukemia (JMML) is an aggressive cancer of young children initiated by mutations in NRAS, KRAS and other genes encoding proteins that modulate Ras signal output. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment and patients with relapsed and refractory disease have dismal outcomes. This trial evaluated the safety and efficacy of trametinib in advanced JMML. Kinase enrichment proteomic analysis was performed using available patient samples pre- or post-treatment with trametinib (NCT03190915) to evaluate the effects on the functional kinome.

2024-04-23 | PXD042328 | Pride

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.

2021-12-17 | GSE167301 | GEO

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

2017-09-01 | GSE86328 | GEO

RECURRENT SETBP1 MUTATIONS IN ATYPICAL CHRONIC MYELOID LEUKEMIA

Project description:RNA-Seq analysis of atypical chronic myeloid leukemia samples We sequenced leukemic mRNA from 13 Atypical Cronic Mieloid Leukemia (aCML) samples by Illumina GAIIx. Transcriptomic profiles, differentially expressed genes and pathway enrichment analysis were obtained comparing 7 SETBP1-mutated samples and 6 non-mutated (WT) samples by using TopHat aligner and SAMMate gene expression quantifier. We focused on the gene expression profile of known coding transcripts. A dataset of 20,907 protein-coding Ensembl Genes was obtained from the RNA-Seq by using the Human Ensembl GTF annotation file vs54 dowloaded from ftp://ftp.ensembl.org/pub/release-54/gtf/homo_sapiens/.

2012-12-07 | E-GEOD-42146 | biostudies-arrayexpress

SETBP1-WT and SETBP1-G870S epigenetic landscapes

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

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Identifying SETBP1 haploinsufficiency molecular pathways to improve patient diagnosis using induced pluripotent stem cells and neural disease modelling.

Project description:Background: SETBP1 Haploinsufficiency Disorder (SETBP1-HD) is characterised by mild to moderate intellectual disability, speech and language impairment, mild motor developmental delay, behavioural issues, hypotonia, mild facial dysmorphisms, and vision impairment. Despite a clear link between SETBP1 mutations and neurodevelopmental disorders the precise role of SETBP1 in neural development remains elusive. We investigate three SETBP1 genetic variants including two pathogenic mutations p.Glu545Ter and SETBP1 p.Tyr1066Ter, resulting in removal of SKI and/or SET domains, and a point mutation p.Thr1387Met in the SET domain. Methods: Genetic variants were introduced into induced pluripotent stem cells (iPSCs) and subsequently differentiated into neurons to model the disease. We measured changes in cellular differentiation, SETBP1 protein localisation, and gene expression changes. Results: The data indicated a change in the WNT pathway, RNA polymerase II pathway and identified GATA2 as a central transcription factor in disease perturbation. In addition, the genetic variants altered the expression of gene sets related to neural forebrain development matching characteristics typical of the SETBP1-HD phenotype. Limitations: The study investigates changes in cellular function in differentiation of iPSC to neural progenitor cells as a human model of SETBP1 HD disorder. Future studies may provide additional information relevant to disease on further neural cell specification, to derive mature neurons, neural forebrain cells, or brain organoids. Conclusions: We developed a human SETBP1-HD model and identified perturbations to the WNT and POL2RA pathway, genes regulated by GATA2. Strikingly neural cells for both the SETBP1 truncation mutations and the single nucleotide variant displayed a SETBP1-HD-like phenotype.

2024-10-02 | GSE262710 | GEO

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