The Contribution of MicroRNAs to the Inflammatory and Neoplastic Characteristics of Erdheim–Chester Disease

Abstract

The pathogenesis of histiocytic neoplasms is driven by mutations activating the MAPK/ERK pathway, but little is known about the transcriptional and post-transcriptional alterations involved in these neoplasms. We analyzed microRNA (miRNA) expression in plasma samples and tissue biopsies of Erdheim–Chester disease (ECD) and Langerhans cell histiocytosis (LCH) patients. In silico analysis revealed a potential role of miRNAs in regulating gene expression in these neoplasms as compared with healthy controls (HC). NanoString analysis revealed 101 differentially expressed plasma miRNAs in 16 ECD patients as compared with 11 HC, 95% of which were downregulated. MiRNAs-15a-5p, -15b-5p, -21-5p, -107, -221-3p, -320e, -630, and let-7 family miRNAs were further evaluated by qRT-PCR in an extended cohort of 32 ECD patients, seven LCH and 15 HC. Six miRNAs (let-7a, let-7c, miR-15a-5p, miR-15b-5p, miR-107 and miR-630) were highly expressed in LCH plasma and tissue samples as compared with ECD. Pathway enrichment analysis indicated the miRNA contribution to inflammatory and pro-survival signaling pathways. Moreover, the let-7 family members were downregulated in untreated ECD patients as compared with HC, while treatment with MAPK/ERK signaling inhibitors for 16 weeks resulted in their upregulation, which was in parallel with the radiologic response seen by PET-CT. The study highlights the potential contribution of miRNA to the inflammatory and neoplastic characteristics of ECD and LCH.

Mutant PIK3CA is a targetable driver alteration in histiocytic neoplasms

“… 13 We recently demonstrated that the PI3K-AKT-mTOR pathway is upregulated in patients with histiocytosis via alterations in microRNAs (miRNAs/miRs) governing PI3K/mTOR activation. 14 Moreover, we previously identified somatic hotspot activating mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), which encodes the p110α protein, the catalytic subunit of PI3K, in several patients with ECD ( Figure 1 A-B). 6 , 15 These mutations have been demonstrated to increase the kinase activity of PIK3CA and contribute to cellular transformation in solid tumor models with concomitant phosphorylation of proteins in the AKT pathway.…”

Case report: Targeted treatment strategies for Erdheim-Chester disease

“…More than 50% of patients are positive for a BRAF mutation. BRAF V600 wild-type ECD lesions have been found to contain somatic mutations in the MAPK/ERK signaling pathway ( 9 ). In these cases, BRAF inhibitor therapy (vemurafenib, dabrafenib) is available under a compassionate use program.…”