Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in JAK2-mutated myeloproliferative neoplasms
| Autor: | Yu-Wei Leu, Kuan Der Lee, Chang Hsien Lu, Yi Yang Chen, Chih-Cheng Chen, Jie Yu You, Chia-Chen Hsu, Chian Pei Li, Jyh Pyng Gau, Hsing-Ying Ho, Cih-En Huang, Jrhau Lung |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Adult Male Cell Survival Apoptosis Translocation Genetic Pathogenesis 03 medical and health sciences 0302 clinical medicine Polycythemia vera HMGA2 Downregulation and upregulation hemic and lymphatic diseases Cell Line Tumor microRNA medicine Humans Hydroxyurea Gene Silencing Protein Kinase Inhibitors Myeloproliferative neoplasm Genetic Association Studies Aged Myeloproliferative Disorders Chromosomes Human Pair 12 biology Essential thrombocythemia HMGA2 Protein Hematology Articles Janus Kinase 2 Middle Aged medicine.disease Prognosis Phenotype MicroRNAs STAT Transcription Factors 030104 developmental biology Gene Expression Regulation 030220 oncology & carcinogenesis Mutation Cancer research biology.protein Female RNA Interference Biomarkers Signal Transduction |
| Zdroj: | Haematologica |
| ISSN: | 1592-8721 0390-6078 |
| Popis: | High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by let-7 microRNA through binding to it’s 3′-untranslated region. Transgenic mice expressing Hmga2 with a truncation of its 3′-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the let-7-HMGA2 axis in myeloproliferative neoplasms, we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent let-7a repression. Ton.JAK2.V617F cells treated with a let-7a inhibitor exhibited further escalation of Hmga2 expression, while a let-7a mimic diminished the Hmga2 transcript level. Hmga2 overexpression conferred JAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of let-7a, downregulated the level of Hmga2, and led to increased apoptosis in Ton.JAK2.V617F cells in a dose-dependent manner. In samples from 151 patients with myeloproliferative neoplasms, there was a modest inverse correlation between the expression levels of let-7a and HMGA2. Overexpression of HMGA2 was detected in 29 (19.2%) of the cases, and it was more commonly seen in patients with essential thrombocythemia than in those with polycythemia vera (26.9% vs. 12.7%, P=0.044). Patients with upregulated HMGA2 showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations in JAK2, MPL and CALR. Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes. |
| Databáze: | OpenAIRE |
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