Abstract
High mobility group AT-hook 2 (HMGA2) is an architectural transcriptional factor that is negatively regulated by Let-7 microRNA. Dysregulated HMGA2 has been shown to exhibit a myeloproliferative phenotype in engineered mice. To decipher the Let-7-HMGA2 axis in myeloproliferative neoplasms (MPN), we studied a cohort of 151 MPN patients. Overexpressed HMGA2 was detected in about one-fifth of the cases, and it was more commonly seen in ET (26.9%, vs. 12.7% in PV, p=0.044). Compared to their counterparts, HMGA2-overexpressing patients had higher platelet counts, increased thromboembolic risk, and inferior thrombosis-free survival. Fluorescence in situ hybridizationanalysis showed that chromosomal translocation was not a major cause of HMGA2 overexpression in MPN patients, yet there was an inverse correlation between the expression levels of let-7a and HMGA2. Furthermore, up-regulation of HMGA2 was significantly associated with MPN patients carrying JAK2V617F mutation. In vitro studies showed that Ba/F3 cells carried JAK2V617F (Ba/F3-JAK2V617F) had decreased let-7a and up-regulated HMGA2. Silencing of HMGA2 in Ba/F3-JAK2V617F cells resulted in growth inhibition coupled with a significant increase in apoptosis. Our findings suggest that, in a subset of JAK2-mutated MPN patients, Let-7-HMGA2 axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.
Disclosures
Hsu: Ministry of Science and Technology (Taiwan): Research Funding; Chang-Gung Memorial Hospital: Employment, Research Funding. Chen:Ministry of Science and Technology (Taiwan): Research Funding; Chang Gung Memorial Hospital, Chiayi branch: Research Funding. Gau:Taipei Veterans General Hospital, Taipei, Taiwan: Employment. Huang:Chang-Gung Memorial Hospital: Employment, Research Funding. You:Lotung Poh-Ai Hospital, Yilan, Taiwan: Employment. Lung:Chang-Gung Memorial Hospital: Employment, Research Funding. Chen:Chang-Gung Memorial Hospital: Employment. Ho:Chang-Gung Memorial Hospital: Employment, Research Funding. Li:Chang-Gung Memorial Hospital: Employment, Research Funding. Lu:Chang Gung Memorial Hospital, Chiayi, Taiwan: Employment. Lee:Chang-Gung Memorial Hospital: Employment, Research Funding.
Hepatic resection for hepatocellular carcinoma in end-stage renal disease patients: Two decades of experience at Chang Gung Memorial Hospital