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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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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 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.

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

SETBP1-WT and SETBP1-G870S epigenetic landscapes

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

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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.

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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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HSP70 inhibition synergizes with MEK inhibition for the treatment of NRAS mutant melanoma

Project description:NRAS-mutant melanoma is currently a challenge to treat. This is due to an absence of inhibitors directed against NRAS, along with acquired and adaptive resistance of this tumor type to inhibitors in the MAPK pathway. Inhibitors to MEK (mitogen-activated protein kinase kinase) have shown some promise for this tumor type. In this work we explored the use of MEK inhibitors for NRAS-mutant melanoma, and at the same time investigated the impact of the brain micro-environment, specifically astrocytes, on the response of a melanoma brain metastatic cell line to MEK inhibition. This led to the surprising finding that astrocytes enhance the sensitivity of melanoma tumors to MEK inhibitors (MEKi). We show that MEKi cause an upregulation of the transcription factor ID3, but this is blocked by conditioned media from astrocytes. We show that silencing ID3 enhances the sensitivity of melanoma to MEK inhibitors, thus mimicking the effect of the brain microenvironment. Moreover, we report that ID3 is a client protein of the chaperone HSP70, and that HSP70 inhibition causes ID3 to misfold and accumulate in a detergent-insoluble fraction in cells. We show that HSP70 inhibitors synergize with MEK inhibitors against NRAS-mutant melanoma, and that this combination significantly enhances the survival of mice in two different models of NRAS-mutant melanoma. These studies highlight ID3 as a mediator of adaptive resistance, and support the combined use of MEK and HSP70 inhibitors for the therapy of NRAS-mutant melanoma.

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S6K2 IS A NOVEL TARGET IN MAPKi-RESISTANT NRAS-MUTANT MELANOMA

Project description:Melanoma is often driven by NRAS mutations. Although oncogenic NRAS activates MAPK signaling, inhibition of this pathway has limited efficacy in NRAS-mutant tumors. As there are limited options to treat these tumors, there is a pressing need to identify NRAS-mutant-specific vulnerabilities that can be therapeutically exploited. Metabolic reprogramming is one of the hallmarks of RAS-mutant tumors, creating a dependency on key metabolic pathways. This dependency could be leveraged to combat these tumors. We discovered that abrogation of S6K2, a mTORC1 effector, triggers accumulation of unsaturated fatty acids, lipid peroxidation and cell death selectively in NRAS-mutant melanoma cells that are resistant to MAPK inhibition. S6K2 depletion induced upregulation of S6K1 and PPAR, triggering apoptotic and ferroptosis-like cell death. Conversely, depletion of S6K1 diminished lipid synthesis and cell proliferation, without eliciting cell death. Collectively, our data indicate that a fine balance between S6K1 and S6K2 activity and metabolic homeostasis is required to prompt cell death of NRAS-mutant melanoma. S6K2 is hence a novel therapeutic target for MAPKi-resistant NRAS-mutant melanoma.

2020-03-06 | GSE127916 | GEO

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