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

SIMPLE SUMMARY: In the last two decades, new molecules, named microRNAs, have been identified. Impairment of microRNA function can lead to the development of diseases such as cancer; therefore, analyzing microRNAs expression, may help to explain the development of diseases. Moreover, these molecules can be obtained easily from blood, with little discomfort to the patient, and this may help to develop them as substances that could help to diagnose diseases and determine response to treatment. Here, we studied how microRNAs are involved in a rare clonal hematological malignancy named Erdheim–Chester disease (ECD). We found a differential expression microRNA signature between ECD patients and healthy controls. Our analysis suggests that reduced expression of microRNAs in ECD results in upregulation of target genes that participate in cell survival signaling and inflammation. This study expands our knowledge of the molecular basis of ECD and may enable improved treatment for affected patients. 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.