Abstract
Erdheim–Chester disease (ECD) is characterized by excessive production and accumulation of histiocytes within multiple tissues and organs. ECD patients harbor recurrent mutations of genes associated with the RAS/RAF/MEK/ERK signaling pathway, particularly, the BRAFV600E mutation. Following our previous finding that miR-15a-5p is the most prominently downregulated microRNA in ECD patients compared to healthy individuals, we elucidated its role in ECD pathogenesis. Bioinformatics analysis followed by a luciferase assay showed that chemokine ligand 10 (CXCL10) is a target gene regulated by miRNA-15a-5p. This was confirmed in 24/34 ECD patients that had low expression of miR-15a-5p concurrent with upregulated CXCL10. Overexpression of miR-15a-5p in cell lines harboring BRAF or RAS mutations (Ba/F3, KG-1a and OCI-AML3) resulted in CXCL10 downregulation, followed by LIN28a and p-ERK signaling downregulation and let-7 family upregulation. Overexpression of miR-15a-5p inhibited cell growth and induced apoptosis by decreasing Bcl-2 and Bcl-xl levels. Analysis of sequential samples from 7 ECD patients treated with MAPK inhibitors (vemurafenib/cobimetinib) for 4 months showed miR-15a-5p upregulation and CXCL10 downregulation. Our findings suggest that miR-15a-5p is a tumor suppressor in ECD through the CXCL10-ERK-LIN28a-let7 axis, highlighting another layer of post-transcriptional regulation in this disease. Upregulation of miR-15a-5p in ECD patients may have a potential therapeutic role.
| Original language | English |
|---|---|
| Pages (from-to) | 1139-1149 |
| Number of pages | 11 |
| Journal | Leukemia |
| Volume | 36 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2022 |
| Externally published | Yes |
Bibliographical note
Publisher Copyright:© 2021, The Author(s).
Funding
This work was supported by the Histiocytosis Association of America research grant. ELD discloses editorial support from Pfizer Inc outside the submitted work. BHD has received research grants from the National Cancer Institute and the American Society of Hematology but declares no commercial conflicts of interest. FC and JH are investigators of an academic trial on the efficacy of cobimetinib on histiocytoses unrelated to the current manuscript. OA-W has served as a consultant for H3B Biomedicine, Foundation Medicine Inc, Merck, Prelude Therapeutics, and Janssen, and is on the Scientific Advisory Board of Envisagenics Inc., AIChemy, and Pfizer Boulder; OA-W has received prior research funding from H3B Biomedicine and LOXO Oncology unrelated to the current manuscript.
| Funders | Funder number |
|---|---|
| AIChemy | |
| American Society of Hematology but declares | |
| Histiocytosis Association of America | |
| Pfizer Boulder | |
| National Cancer Institute | P30CA008748 |
| Histiocytosis Association | 2019-2020 |
