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

UID: 10687

Author(s): Berres, Marie-Luise, Hogstad, Brandon, Chakraborty, Rikhia, Allen, Carl E, Merad, Miriam

Description
Summary from GEO: " 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."

Overall design from GEO: "18 samples; 2-3 replicates per organ and genotype; WT are littermate control reference relative to CD11c-Cre/BRAFV600E(flox) specimens"
Subject of Study
Mus musculus
Subject(s)
bcl-X Protein
Dendritic Cells
Histiocytosis, Langerhans-Cell
Mitogen-Activated Protein Kinase Kinases
Proto-Oncogene Proteins B-raf
Receptors, CCR7
OncoTree Cancer Type(s)
Langerhans Cell Histiocytosis
Access via GEO

CEL expression profiling by array
Accession #: GSE108251

Access via BioProject

Additional information about overall initiative
Accession #: PRJNA422980

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus and BioProject databases provide open access to these files.
Associated Publications
Hogstad B, Berres M, Chakraborty R, et al. RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. Journal of Experimental Medicine. 2018; 215(1):319-336.
Data Type
Genomic
Equipment Used
[MoGene-1_0-st] Affymetrix Mouse Gene 1.0 ST Array [transcript (gene) version]
Software Used
GEO2R

Use GEO2R to compare two or more groups of Samples in order to identify genes that are differentially expressed across experimental conditions. Results are presented as a table of genes ordered by significance.

Dataset Format(s)
TAR, CEL
Dataset Size
68.9 MB (TAR of CEL)
Data Catalog Record Updated
2021-10-12