Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Vemurafenib acts as molecular switch in Langerhans Cell Histiocytosis

ABSTRACT: Langerhans cell histiocytosis (LCH) is a neoplasm marked by the accumulation of CD1a+CD207+ cells. It is most commonly driven by a somatic activating mutation in the BRAF kinase (BRAFV600E). Multisystem disease with risk-organ involvement requires intensive chemotherapy, making BRAF-inhibitors an attractive option. Here, we present a comprehensive analysis of the course of an LCH patient treated with the combination of vemurafenib with salvage chemotherapy who achieved complete clinical and molecular remission. We conclusively show that there is no relationship between blood-BRAF levels and clinical presentation during treatment with vemurafenib, but that vemurafenib leads to a fast, efficient, but reversible inhibition of clinical manifestations of high-risk LCH such as cytopenia, fever, and hypoproteinemia. In line, serum levels of inflammatory cytokines exactly mirror vemurafenib administration. Genotyping for the BRAFV600E mutation shows its presence in multiple hematopoietic cell types, including NK cells and granulocytes. Single-cell transcriptome analysis of peripheral blood and bone marrow cells at time of diagnosis and during treatment indicate that RAF-inhibition abrogates the expression of inflammatory cytokines previously implicated in LCH. Together, our data suggest that while the CD1a+CD207+ histiocytes are the hallmark of LCH, other BRAF-mutated cells themselves contribute significantly to morbidity in patients with multisystem LCH.

ORGANISM(S): Homo sapiens

PROVIDER: GSE175480 | GEO | 2021/09/23

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Circulating CD1c+ myeloid dendritic cells are precursors to Langerhans cell histiocytosis (LCH) lesion CD1a+CD207+cells

Project description:Expression data from LCH lesion subpopulations and healthy donors' peripheral blood specimens Langerhans cell histiocytosis (LCH) is a myeloproliferative disorder that is characterized by the inflammatory lesions with pathogenic CD1a+CD207+ dendritic cells (DCs). BRAFV600E and other somatic activating MAPK gene mutations have been identified in differentiating bone marrow and blood myeloid cells, but the origin of the LCH lesion CD1a+CD207+DCs and mechanisms of lesion formation remain incompletely defined. In order to identify candidate LCH CD1a+CD207+DCs’ precursor populations, gene expression profiles of LCH lesion CD1a+CD207+DCs were first compared to established gene signatures from human myeloid cell subpopulations. Interestingly, the CD1c+ myeloid DC (mDC) gene signature was most enriched in the LCH CD1a+CD207+DC’ transcriptome. Additionally, the BRAFV600E allele was not only localized to CD1a+CD207-DCs and CD1a+CD207+DCs, but it was also identified in CD1c+mDCs in LCH lesions. Transcriptomes of CD1a+CD207-DCs were nearly indistinguishable from CD1a+CD207+DCs (both CD207low and CD207high subpopulations). Transcription profiles of LCH lesion CD1a+CD207+DCs and peripheral blood CD1c+mDCs from healthy donors were compared to identify potential LCH DC-specific biomarkers. HLADQB2 expression was significantly increased in LCH lesion CD1a+CD207+DCs compared to circulating CD1c+mDCs from healthy donors, and HLA-DQB2 antigen was identified on LCH lesion CD1a+CD207- and CD1a+CD207+DCs as well as on CD1c+(CD1a+CD207-) mDCs, but not in any other lesion myeloid subpopulations. Interestingly, HLADQB2 expression was specific to peripheral blood of patients with BRAFV600E+ peripheral blood mononuclear cells (PBMC), and HLA-DQB2+CD1c+blood cells were highly enriched for the BRAFV600E in these patients. These data support a model where blood CD1c+mDCs with activated ERK migrate to lesion sites where they differentiate into pathogenic CD1a+CD207+ DCs.

2020-01-21 | GSE122476 | GEO

Circulating CD1c+ myeloid dendritic cells are precursors to Langerhans cell histiocytosis (LCH) lesion CD1a+CD207+cells

2020-01-21 | GSE122674 | GEO

Notch is active in Langerhans Cell Histiocytosis and confers pathognomonic features on dendritic cells.

Project description:Langerhans cell histiocytosis (LCH) is a disease characterized by the accumulation of eponymous CD1a+ Langerin+ Langerhans-cell (LC)-like dendritic cells (DC) of largely unknown origin. Here we have performed comparative transcriptome analysis of highly purified CD207+/CD1a+ Langerhans cell histiocytosis (LCH) cells derived from different locations and disease courses and three major human dendritic cell lineages: epidermal Langerhans cells, myeloid dendritic cells (mDC1) and plasmacytoid dendritic cells (pDC) in order to investigate the relationship between LCH cells and naturally occurring dendritic cells. Data obtained indicate that LCH cells form a distinct DC entity. Furthermore, we have identified transcripts that are uniquely expressed by LCH cells in comparison to LC, mDC1, and pDC, and induce LCH-specific features in human DC. Primary cells were isolated from peripheral blood (mDC1 and pDC), skin (epidermal Langerhans cells) and CD207+/CD1a+ Langerhans cell histiocytosis (LCH) cells derived from different locations. RNA was isolated from these cells ex vivo.

2012-10-24 | E-GEOD-35340 | biostudies-arrayexpress

RAF/MEK/extracellular signal–related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions

Project description:Expression data from dendritic cell subsets derived or sorted from control littermate and CD11c-Cre/BRAFV600E(flox-CA) mice Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasia characterized by granulomatous lesions containing pathological CD207+ dendritic cells (DCs) with constitutively activated mitogen-activated protein kinase (MAPK) pathway signaling. Approximately 60% of LCH patients harbor somatic BRAFV600E mutations localizing to CD207+ DCs within lesions. However, the mechanisms driving BRAFV600E+ LCH cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal–related kinase activity induced by BRAFV600E inhibits C-C motif chemokine receptor 7 (CCR7)–mediated DC migration, trapping DCs in tissue lesions. Additionally, BRAFV600E increases expression of BCL2-like protein 1 (BCL2L1) in DCs, resulting in resistance to apoptosis. Pharmacological MAPK inhibition restores migration and apoptosis potential in a mouse LCH model, as well as in primary human LCH cells. We also demonstrate that MEK inhibitor-loaded nanoparticles have the capacity to concentrate drug delivery to phagocytic cells, significantly reducing off-target toxicity. Collectively, our results indicate that MAPK tightly suppresses DC migration and augments DC survival, rendering DCs in LCH lesions trapped and resistant to cell death.

2017-12-20 | GSE108251 | GEO

Notch is active in Langerhans Cell Histiocytosis and confers pathognomonic features on dendritic cells.

2012-10-24 | GSE35340 | GEO

Ezrin inhibition overcomes acquired resistance to vemurafenib in BRAFV600E-mutated colon cancer and melanoma cells in vitro

Project description:In spite of the advancements in targeted therapy for BRAFV600E-mutated metastatic colorectal cancer (mCRC), the development of resistance to BRAFV600E inhibition limits the response rate and durability of the treatment. Better understanding of the resistance mechanisms to BRAF inhibitors will facilitate the design of novel pharmacological strategies for BRAF-mutated mCRC. The aim of this study was to identify novel protein candidates involved in acquired resistance to BRAFV600E inhibitor vemurafenib in BRAFV600E-mutated colon cancer cells using an integrated proteomics approach. Our study suggests a role of ezrin in acquired resistance to vemurafenib in colon cancer and melanoma cells carrying BRAFV600E mutation and supports further pre-clinical and clinical studies to explore the benefits of combined BRAF inhibitors and actin-targeting drugs as a potential therapeutic approach for BRAFV600E-mutated cancers.

2023-08-29 | PXD042499 | Pride

Expression data from BRAFV600E A375 melanoma cells treated with vehicle or vemurafenib

2014-05-20 | GSE42872 | GEO

The secretome features associated with the development of re-sistance to vemurafenib in BRAFV600E mutated colon cancer cells

Project description:Patients with metastatic colorectal cancer (mCRC) carrying BRAFV600E mutation have worse response to chemotherapy and poor prognosis. The aim of this study was to conduct for the first time comparative proteomics profiling of the secretome from vemurafenib-sensitive vs. resistant colon cancer cells harboring BRAFV600E mutation in order to identify specific secretory features potentially associated with the development of resistance to vemurafenib. Towards this aim, we employed a label-free quantitative LC-MS/MS analysis. Obtained results pointed to aberrant regulation of DNA replication and the endoplasmic reticulum stress as the major secretome features associated with chemoresistant phenotype. Further studies are required to investigate diagnostic values of these proteins in the clinical setting and to examine their roles in acquired resistance to BRAF inhibition not only in colon cancer but also in other BRAF mutated cancers.

2023-04-29 | PXD039766 | Pride

Diverse and Targetable Kinase Alterations Drive Histiocytic Neoplasms

Project description:Histiocytic neoplasms are clonal, hematopoietic disorders characterized by an accumulation of abnormal, monocyte-derived dendritic cells or macrophages in Langerhans Cell (LCH) and non-Langerhans (non-LCH) histiocytoses, respectively. The discovery of BRAFV600E mutations in ~50% of these patients provided the first molecular therapeutic target in histiocytosis. However, recurrent driving mutations in the majority of BRAFV600E-wildtype, non-LCH patients are unknown, and recurrent cooperating mutations in non-MAP kinase pathways are undefined for the histiocytic neoplasms. Through combined whole exome and transcriptome sequencing, we identified recurrent kinase fusions involving BRAF, ALK, and NTRK1, as well as recurrent, activating MAP2K1 and ARAF mutations in BRAFV600E-wildtype, non-LCH patients. In addition to MAP kinase pathway lesions, recurrently altered genes involving diverse cellular pathways were identified. Treatment of MAP2K1- and ARAF-mutated, non-LCH patients using MEK and RAF inhibitors, respectively, resulted in clinical efficacy demonstrating the importance of detecting and targeting diverse kinase alterations in these disorders. 13 patient samples were analyzed by RNA-seq and had 2 replicates.

2015-11-11 | E-GEOD-74442 | biostudies-arrayexpress

Expression data from BRAFV600E A375 melanoma cells treated with vehicle or vemurafenib

Project description:Vemurafenib is a BRAF inhibitor with specificity for the most common BRAF mutant encountered in melanomas (BRAFV600E). Vemurafenib suppresses the proliferation of BRAF mutant human melanoma cells by suppressing downstream activation of the MEK/ERK mitogen activated protein kinases. We used microarrays to examine the transcriptional response of a vemurafenib-sensitive BRAFV600E human melanoma cell line (A375) to vemurafenib in order to further delineate the mechanisms by which BRAFV600E drives cell proliferation and energy metabolism in human melanoma. BRAFV600E A375 human melanoma cells were treated with vehicle (0.1% DMSO) or 10 uM vemurafenib for 24 h after which total RNA was extracted. Cells were prepared and RNA was extracted in 3 separate batches (three different cell stocks on three separate days) providing three independent replicates (n=3). Paired replicates (prepared from the same stock of cells on the same day) are denoted by A, B and C.

2014-05-20 | E-GEOD-42872 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data