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Target Concepts:
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Query: UMLS:C0019621 (
Langerhans cell histiocytosis
)
3,250
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
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
BRAF
V600E mutations localizing to CD207
+
DCs within lesions. However, the mechanisms driving
BRAF
V600E
+
LCH
cell accumulation in lesions remain unknown. Here we show that sustained extracellular signal-related kinase activity induced by
BRAF
V600E inhibits
C-C
motif chemokine receptor 7 (CCR7)-mediated DC migration, trapping DCs in tissue lesions. Additionally,
BRAF
V600E 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.
...
PMID:RAF/MEK/extracellular signal-related kinase pathway suppresses dendritic cell migration and traps dendritic cells in Langerhans cell histiocytosis lesions. 2926 18
