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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Role of adhesion receptors in mast cell disease-evolution

ABSTRACT: Systemic mastocytosis (SM) is an incurable neoplasm characterized by abnormal accumulation of neoplastic mast cells (MC) in vascularized organs. In indolent SM, MC express several different adhesion-molecules including CD2 and CD58, and form focal tissue-aggregates, whereas in advanced SM, MC often lack CD2 and produce a more diffuse infiltration-pattern. To explore the functional role of CD2 in the pathology of SM, stable CD2+ and CD2− subclones of the human MC-leukemia cell line HMC-1 were generated and injected intraperitoneally into pfp/rag2 mice. CD2+ HMC-1 cells formed solid mastocytomas in the peritoneum and lungs, whereas CD2− cells produced diffuse infiltration. CD2+ and CD2− HMC-1 subclones all displayed the driver-mutant KIT D816V, exhibited the same growth-kinetics, and displayed identical adhesion-receptors including CD44 and selectin-ligands. To explore the mechanism of organ invasion, E- and P-selectin-deficient scid mice (scid-select) were employed. While massive HMC-1 infiltrates were detected in the lungs of control mice, infiltration was markedly reduced or absent in scid-select mice. The invasion-receptor CD44 was detectable in all MC infiltrates, with most abundant expression in the invasion-front. Together, our data show that selectins mediate organ-invasion of MC and CD2-CD58 interactions contribute to a more focal infiltration-pattern which is lost during progression to MC leukemia. HMC1 cells were sorted by FACS for expression of CD2 surface expression. 2 subclones were obtained (CD2+ or CD2-) and compared by gene expression profiling using U133 plus 2.0 GeneChips

ORGANISM(S): Homo sapiens

SUBMITTER: Martin Bilban

PROVIDER: E-GEOD-33504 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Role of adhesion receptors in mast cell disease-evolution

Project description:Systemic mastocytosis (SM) is an incurable neoplasm characterized by abnormal accumulation of neoplastic mast cells (MC) in vascularized organs. In indolent SM, MC express several different adhesion-molecules including CD2 and CD58, and form focal tissue-aggregates, whereas in advanced SM, MC often lack CD2 and produce a more diffuse infiltration-pattern. To explore the functional role of CD2 in the pathology of SM, stable CD2+ and CD2− subclones of the human MC-leukemia cell line HMC-1 were generated and injected intraperitoneally into pfp/rag2 mice. CD2+ HMC-1 cells formed solid mastocytomas in the peritoneum and lungs, whereas CD2− cells produced diffuse infiltration. CD2+ and CD2− HMC-1 subclones all displayed the driver-mutant KIT D816V, exhibited the same growth-kinetics, and displayed identical adhesion-receptors including CD44 and selectin-ligands. To explore the mechanism of organ invasion, E- and P-selectin-deficient scid mice (scid-select) were employed. While massive HMC-1 infiltrates were detected in the lungs of control mice, infiltration was markedly reduced or absent in scid-select mice. The invasion-receptor CD44 was detectable in all MC infiltrates, with most abundant expression in the invasion-front. Together, our data show that selectins mediate organ-invasion of MC and CD2-CD58 interactions contribute to a more focal infiltration-pattern which is lost during progression to MC leukemia.

2013-01-01 | GSE33504 | GEO

KIT D816V mast cells derived from induced pluripotent stem cells recapitulate systemic mastocytosis transcriptional profile

Project description:Mast cells (MC) represent a population of hematopoietic cells with a key role in innate and adaptive immunity and are well known for their detrimental role in allergic responses. Yet, MC occur in low abundance which hampers their detailed molecular analysis. Here, we capitalized on the potential of induced pluripotent stem (iPS) cells to give rise to all cells of the body and established a robust protocol for human iPS cell differentiation towards MC. Relying on a panel of systemic mastocytosis (SM) patient-specific iPS cell lines carrying the KIT D816V mutation, we generated functional MC that recapitulate SM disease features: increased number of MC, abnormal maturation kinetics and activated phenotype, CD2 and CD30 surface expression and a transcriptional signature characterized by upregulated expression of innate and inflammatory response genes. Therefore, human iPS cell-derived MC are a reliable and close-to-human tool for disease modeling and pharmacological screening to explore novel MC therapeutics.

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Mast cell-derived SAMD14 is a novel regulator of the human prostate tumor microenvironment

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2021-03-12 | PXD022782 | Pride

Differential 5-methylcytosine and 5-hydroxymethylcytosine in Parkinson’s and Alzheimer’s Disease.

Project description:Background: 5-methylcytosine (5-mC) and its oxidized form, 5-hydroxymethylcytosine (5-hmC), are distinct epigenetic marks that help regulate gene expression in the mammalian brain. Existing studies have identified associations between 5-mC and neurodegenerative disease, but little work has examined the potential role of 5-hmC in Parkinson’s disease (PD) or Alzheimer’s disease (AD). Here, we utilized PD postmortem brain tissue and a public dataset from postmortem AD brains to analyze the effect of neurodegenerative disease on paired 5-mC and 5-hmC levels. Results: In PD samples, we measured genome-wide 5-mC and 5-hmC from control (n=3) and PD (n=6) brains using the Illumina EPIC array combined with bisulfite and oxidative bisulfite treatments (BS/oxBS-EPIC). In publicly sourced data, genome-wide 5-mC and 5-hmC were measured from control (n=25) and AD (n=62) human entorhinal cortex tissue using the Illumina 450K array combined with bisulfite and oxidative bisulfite treatment (BS/oxBS-450K). Paired 5-mC and 5-hmC beta values were generated using a custom pipeline of bioinformatics tools, and we modeled the effect of disease on paired 5-mC and 5-hmC data using a mixed effects beta regression model with a random effect for ID and an interaction term between disease category and DNA modification category (“5-mC” or “5-hmC”). We identified a number of CpG probes (AD: n=699, PD: total n = 80) that showed a significant interaction between disease status and DNA modification category (p-value < 2.4x10-7). Conclusions: While our PD data requires additional validation, our analyses suggest that there are widespread shifts in the balance between 5-mC and 5-hmC in Parkinson’s and Alzheimer’s disease.

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