- Chih-Cheng Chen1,
- Jie-Yu You2,
- Jrhau Lung3,
- Cih-En Huang1,
- Yi-Yang Chen3,
- Yu-Wei Leu4,
- Hsing-Ying Ho3,
- Chian-Pei Li3,
- Chang-Hsien Lu1,
- Kuan-Der Lee1,
- Chia-Chen Hsu5 and
- Jyh-Pyng Gau6,*
- 1 Chang-Gung Memorial Hospital, Chiayi branch and College of Medicine, Chang Gung University, Taiwan;
- 2 Lotung Poh-Ai Hospital, Yilan and School of Medicine, National Yang-Ming University, Taiwan;
- 3 Chang-Gung Memorial Hospital, Chiayi branch, Taiwan;
- 4 National Chung-Cheng University, Chiayi, Taiwan;
- 5 Chang Gung Memorial Hospital, Chiayi branch, Taiwan;
- 6 Taipei Veterans General Hospital and School of Medicine, National Yang-Ming University, Taiwan
- ↵* Corresponding author; email:
High mobility group AT-hook 2 (HMGA2) is an architectural transcriptional factor that is negatively regulated by Let-7 microRNA through binding to its 3-untranslated region (3-UTR). Transgenic mice expressing HMGA2 with a truncation of its 3-UTR has been shown to exhibit a myeloproliferative phenotype. To decipher the Let-7-HMGA2 axis in myeloproliferative neoplasms (MPN), we employed an in vitro model supplemented with clinical correlation. Ba/F3 cells with inducible JAK2V617F expression (Ton.JAK2.V617F cells) showed up-regulation 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 a survival advantage through inhibited apoptosis. Pan-JAK inhibitor INC424 increased the expression of let-7a, down-regulated 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 MPN, there was a modest invest 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). MPN patients harboring up-regulated HMGA2 showed in increased propensity of developing major thrombotic events, and they were more likely to harbor one of the 3 driver mutations. Our findings suggest that, in a subset of MPN patients, Let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.
- Received August 10, 2016.
- Accepted December 30, 2016.
- Copyright © 2017, Ferrata Storti Foundation