miR-543 regulates the epigenetic landscape of myelofibrosis by targeting TET1 and TET2

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Fuentes-Mattei, Enrique ^[1] ; Bayraktar, Recep ^[1] ; Manshouri, Taghi ^[2] ; Silva, Andreia M. ^{[1, 3, 4, 5]} ; Ivan, Cristina ^{[1, 6]} ; Gulei, Diana ^{[1, 7, 8]} ; Fabris, Linda ^[1] ; do Amaral, Nayra Soares ^{[1, 9]} ; Mur, Pilar ^[10] ; Perez, Cristina ^{[1, 11]} ; Torres-Claudio, Elizabeth ^{[1, 12]} ; Dragomir, Mihnea P. ^{[1, 7, 13]} ; Badillo-Perez, Adriana ^[14] ; Knutsen, Erik ^{[1, 15]} ; Narayanan, Pranav ^[1] ; Golfman, Leonard ^[16] ; Shimizu, Masayoshi ^[1] ; Zhang, Xinna ^{[6, 17]} ; Zhao, Wanke ^[18] ; Ho, Wanting Tina ^[18] ; Estecio, Marcos Roberto ^{[19, 20]} ; Bartholomeusz, Geoffrey ^[1] ; Tomuleasa, Ciprian ^[21] ; Berindan-Neagoe, Ioana ^{[7, 8]} ; Zweidler-McKay, Patrick A. ^{[16, 22]} ; Estrov, Zeev ^[2] ; Zhao, Zhizhuang J. ^[18] ; Verstovsek, Srdan ^[2] ; Calin, George A. ^{[1, 6]} ; Redis, Roxana S. ^{[1, 23]}

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^[1] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 - USA

^[2] Univ Texas MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 - USA

^[3] Univ Porto, Inst Engn Biomed INEB, Porto - Portugal

^[4] Univ Porto, i3S, Porto - Portugal

^[5] Univ Porto, Inst Biomed Sci Abel Salazar ICBAS, Porto - Portugal

^[6] Univ Texas MD Anderson Canc Ctr, Ctr RNA Interference & Noncoding RNAs, Houston, TX 77030 - USA

^[7] Univ Med & Pharm Iuliu Hatieganu, Res Ctr Funct Genom Biomed & Translat Med, Cluj Napoca - Romania

^[8] Oncol Inst, Dept Funct Genom, Cluj Napoca - Romania

^[9] AC Camargo Canc Ctr, Dept Investigat Pathol, Mol Morphol Lab, Sao Paulo - Brazil

^[10] Bellvitge Biomed Res Inst IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Barcelona - Spain

^[11] Univ Puerto Rico, Mayaguez Campus, Mayaguez, PR - USA

^[12] Univ Puerto Rico, Med Sci Campus, San Juan, PR 00936 - USA

^[13] Carol Davila Univ Med & Pharm, Fundeni Hosp, Dept Surg, Bucharest - Romania

^[14] Univ Puerto Rico, Rio Piedras Campus, San Juan, PR 00936 - USA

^[15] Arctic Univ Norway, Fac Hlth Sci, Dept Med Biol, Tromso - Norway

^[16] Univ Texas MD Anderson Canc Ctr, Dept Pediat, Houston, TX 77030 - USA

^[17] Indiana Univ, Med & Mol Genet Dept, Indianapolis, IN 46204 - USA

^[18] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK - USA

^[19] Univ Texas MD Anderson Canc Ctr, Dept Epigenet & Mol Carcinogenesis, Houston, TX 77030 - USA

^[20] Univ Texas MD Anderson Canc Ctr, Ctr Canc Epigenet, Houston, TX 77030 - USA

^[21] Univ Med & Pharm Luliu Hatieganu, Oncol Inst Ion Chiricuta, Dept Hematol, Cluj Napoca - Romania

^[22] ImmunoGen Inc, Boston, MA - USA

^[23] ProQR Therapeut, Leiden - Netherlands

• Tipo de documento: Artigo Científico
• Fonte: JCI INSIGHT; v. 5, n. 1 JAN 16 2020.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 16/09349-4 - Validação e estudos funcionais de miRNAs diferencialmente expressos em carcinomas serosos de alto grau de pacientes com distintas evoluções clínicas
• Beneficiário: Nayra Soares do Amaral
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado