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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
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:
It is part of: JCI Insight, 2020, vol. 5, num. 1
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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