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Data independent MS phenotyping of melanoma tissue specimens

ABSTRACT: Phenotyping of Stage III BRAF or NRAS mutant melanoma tissue specimens to predict drug response and patient survival

INSTRUMENT(S): TripleTOF 6600

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Melanocyte, Skin

DISEASE(S): Melanoma

SUBMITTER: Christoph Krisp

LAB HEAD: Mark P Molloy

PROVIDER: PXD007083 | Pride | 2018-10-11

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	BRAFNRAS_IonLib.group	Other
	BRAF_142.wiff	Wiff
	BRAF_142.wiff.scan	Wiff
	BRAF_16.wiff	Wiff
	BRAF_16.wiff.scan	Wiff

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1 - 5 of 82

Publications

Proteomic phenotyping of metastatic melanoma reveals putative signatures of MEK inhibitor response and prognosis.

Krisp Christoph C Parker Robert R Pascovici Dana D Hayward Nicholas K NK Wilmott James S JS Thompson John F JF Mann Graham J GJ Long Georgina V GV Scolyer Richard A RA Molloy Mark P MP

British journal of cancer 20180817 6

<h4>Background</h4>Genotyping of melanomas is used to identify patients for treatment with BRAF and MEK inhibitors, but clinical responses are highly variable. This study investigated the utility of protein expression phenotyping to provide an integrated assessment of gene expression programs in BRAF/NRAS melanoma which would be useful for prognosis and may predict response to MEK inhibition.<h4>Methods</h4>Mass spectrometry profiling of early passage cell lines established from Stage III cutane ...[more]

PMID: 30116025

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Pharmacological Targeting of Casein Kinase 1δ Suppresses Oncogenic NRAS-Driven Melanoma

Project description:Activating mutations in NRAS account for 20-30% of melanoma, yet effective anti-NRAS therapies are still lacking. In this study, we unveil the casein kinase 1δ (CK1δ) as an uncharacterized regulator of oncogenic NRAS mutations, specifically Q61R and Q61K, which are the most prevalent NRAS mutations in melanoma. The genetic ablation or pharmacological inhibition of CK1δ markedly destabilizes NRAS mutants and suppresses their oncogenic functions. Moreover, we identify USP46 as a bona fide deubiquitinase of NRAS mutants. Mechanistically, CK1δ directly phosphorylates USP46 and activates its deubiquitinase activity towards NRAS mutants, thus promoting oncogenic NRAS-driven melanocyte malignant transformation and melanoma progression in vitro and in vivo. Our findings underscore the significance of the CK1δ-USP46 axis in stabilizing oncogenic NRAS mutants and provide preclinical evidence that targeting this axis holds promise as a therapeutic strategy for human melanoma harboring NRAS mutations.

2024-09-20 | PXD046277 | Pride

Effect of DNMT3A R882H mutation or WT on gene expression in hematopoietic stem/progenitor cells with NRAS G12D co-transduction (Microarray)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational â??hotspotâ?? at Arg882 (i.e., DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of â??stemnessâ?? gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided microarray data showing effect of R882H-mutated or WT DNMT3A on gene expression among HSPCs with NRAS G12D co-transduction. Microarray analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) at day 12 or day 16 post-transduction.

2016-06-23 | E-GEOD-71437 | biostudies-arrayexpress

Effect of DNMT3A R882H mutation or WT expression on global DNA methylation patterns of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (eRRBS)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided enhanced Reduced Representation Bisulfite Sequencing (eRRBS) DNA methylome profiling data showing effect of DNMT3A R882H mutation or WT expression on hematopoietic stem/progenitor cells with NRAS G12D co-transduction. eRRBBs DNA methylome analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) at day 16 post-transduction.

2016-06-23 | E-GEOD-71473 | biostudies-arrayexpress

Effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction (ChIP-seq)

Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided H3K4me1, H3K27ac and H3K79me2 ChIP-seq profiling data showing effect of DNMT3A R882H mutation or WT expression on epigenetic landscapes of hematopoietic stem/progenitor cells with NRAS G12D co-transduction. ChIP-seq analysis of Lin- enriched hematopoietic stem/progenitor cells with retroviral infection of NRAS G12D alone (EV-RAS), DNMT3A R882H with NRAS G12D (RH-RAS) or DNMT3A WT with NRAS G12D (WT-RAS) 3 weeks post-transduction. Antibodies of H3K4me1, H3K27ac and H3K79me2 were used.

2016-06-23 | E-GEOD-71472 | biostudies-arrayexpress

Gene expression profiling of oncogenic NRAS driven mouse melanomas that have developed resistance to NRAS withdrawal

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RNA sequencing expression analysis of murine MLL-AF9;NRAS acute myeloid leukemia cells silenced for E2-2.

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Data independent MS phenotyping of patient derived melanoma cell lines

Project description:Phenotyping of patient derived Stage III and IV melanoma cell lines to predict drug response

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Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition.

Project description:We utilize hydrogen deuterium exchange mass spectrometry (HDX-MS) to probe the solvation and conformational dynamics of HLA-A*01:01/hβ2m complexes that are emptied or loaded with NRAS Q61K peptide, as well as wild-type (Q61) and three additional, common neoepitopes (Q61H, Q61L, Q61R).

2023-11-30 | PXD044838 | Pride

Systematic Evaluation and Optimization of Protein Extraction Parameters in Diagnostic FFPE Specimens

Project description:Objectives: Formalin-fixed paraffin-embedded (FFPE) tissue is the standard material for di-agnostic pathology but poses relevant hurdles to accurate protein extraction due to cross-linking and chemical alterations. While numerous extraction pro-tocols and chemicals have been described, systematic comparative analyses are limited. Various parameters were thus investigated in their qualitative and quantitative effects on protein extraction (PE) efficacy. Special emphasis was put on preservation of membrane proteins (MP) as key subgroup of func-tionally relevant proteins. Methods: Using the example of urothelial carcinoma, FFPE tissue sections were subjected to various deparaffinization, protein extraction and antigen retrieval protocols and buffers as well as different extraction techniques. Performance was meas-ured by protein concentration and western blot analysis of cellular compart-ment markers as well as liquid chromatography-coupled mass spectrometry (LC-MS). Results: Commercially available extraction buffers showed reduced extraction of MPs and came at considerably increased costs. On-slide extraction did not improve PE whereas several other preanalytical steps could be simplified. Systematic variation of temperature and exposure duration demonstrated a quantitatively relevant corridor of optimal antigen retrieval. Conclusions: Preanalytical protein extraction can be optimized at various levels to improve unbiased protein extraction and to reduce time and costs.

2022-05-19 | PXD029133 | Pride

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