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Title: | MiR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2 |
Author: | Fuentes-Mattei, Enrique Bayraktar, Recep Manshouri, Taghi Silva, Andreia M. Ivan, Cristina Gulei, Diana Fabris, Linda Soares do Amaral, Nayra Mur, Pilar Pérez, Cristina Torres Claudio, Elisabeth Dragomir, Mihnea P. Badillo Pérez, Adriana Knutsen, Eric Narayanan, Pranav Golfman, Leonard Shimizu, Masayoshi Zhang, Xinna Zhao, Wanke Ho, Wanting Tina Estecio, Marcos Roberto Bartholomeusz, Geoffrey Tomuleasa, Criprian Berindan-Neagoe, Ioanna Zweidler-MCkay, Patrick A. Estrov, Zeev Zhao, Zhizhuang J. Verstovsek, Srdan Calin, George A. Redis, Roxana S. |
Keywords: | Mielofibrosi Hematopoesi Myelofibrosis Hematopoiesis |
Issue Date: | 16-Jan-2020 |
Publisher: | American Society for Clinical Investigation |
Abstract: | Myelofibros is (MF) is a myeloproliferative neoplasm characterized by cytopenia and extramedullary hematopoiesis, resulting in splenomegaly. Multiple pathological mechanisms (e.g., circulating cytokines and genetic alterations, such as JAK(V617F) mutation) have been implicated in the etiology of MF, but the molecular mechanism causing resistance to JAK(V617F) inhibitor therapy remains unknown. Among MF patients who were treated with the JAK inhibitor ruxolitinib, we compared noncoding RNA profiles of ruxolitinib therapy responders versus nonresponders and found miR-S43 was significantly upregulated in non responders. We validated these findings by reverse transcription-quantitative PCR. in this same cohort, in 2 additional independent MF patient cohorts from the United States and Romania, and in a JAK2(V617F) mouse model of MF. Both in vitro and in vivo models were used to determine the underlying molecular mechanism of miR-543 in MF. Here, we demonstrate that miR-543 targets the dioxygenases ten-eleven translocation 1 (TET1) and 2 (TET2) in patients and in vitro, causing increased levels of global 5-methylcytosine, while decreasing the acetylation of histone 3, STAT3, and tumor protein p53. Mechanistically, we found that activation of STAT3 by JAKs epigenetically controls miR-543 expression via binding the promoter region of miR-543. Furthermore, miR-543 upregulation promotes the expression of genes related to drug metabolism, including CYP3A4, which is involved in ruxolitinib metabolism. Our findings suggest miR-543 as a potentially novel biomarker for the prognosis of MF patients with a high risk of treatment resistance and as a potentially new target for the development of new treatment options. |
Note: | Reproducció del document publicat a: https://doi.org/10.1172/jci.insight.121781 |
It is part of: | JCI Insight, 2020, vol. 5, num. 1 |
URI: | http://hdl.handle.net/2445/173249 |
Related resource: | https://doi.org/10.1172/jci.insight.121781 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
Files in This Item:
File | Description | Size | Format | |
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Fuentes-MatteiE.pdf | 16.6 MB | Adobe PDF | View/Open |
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