title: Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype inJAK2-mutated myeloproliferative neoplasms.
abstract: High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated bylet-7microRNA through binding to it's 3'-untranslated region. Transgenic mice expressingHmga2with a truncation of its 3'-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher thelet-7-HMGA2axis in myeloproliferative neoplasms, we employed anin vitromodel supplemented with clinical correlation. Ba/F3 cells with inducibleJAK2V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrentlet-7arepression. Ton.JAK2.V617F cells treated with alet-7ainhibitor exhibited further escalation ofHmga2expression, while alet-7amimic diminished theHmga2transcript level.Hmga2overexpression conferredJAK2-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression oflet-7a, downregulated the level ofHmga2, 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 oflet-7aandHMGA2Overexpression ofHMGA2was 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%vs12.7%,P=0.044). Patients with upregulatedHMGA2showed an increased propensity for developing major thrombotic events, and they were more likely to harbor one of the 3 driver myeloproliferative neoplasm mutations inJAK2,MPLandCALROur findings suggest that, in a subset of myeloproliferative neoplasm patients, thelet-7-HMGA2axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.|College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Chih-Cheng
authors.initials: CC
authors.lastname: Chen
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Lotung Poh-Ai Hospital, Yilan, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jie-Yu
authors.initials: JY
authors.lastname: You
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Jrhau
authors.initials: J
authors.lastname: Lung
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.|College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Cih-En
authors.initials: CE
authors.lastname: Huang
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Yi-Yang
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Department of Life Science and Institute of Molecular Biology, National Chung Cheng University, Chiayi, Taiwan.
authors.forename: Yu-Wei
authors.initials: YW
authors.lastname: Leu
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Hsing-Ying
authors.initials: HY
authors.lastname: Ho
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.
authors.forename: Chian-Pei
authors.initials: CP
authors.lastname: Li
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.|College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Chang-Hsien
authors.initials: CH
authors.lastname: Lu
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan.|College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
authors.forename: Kuan-Der
authors.initials: KD
authors.lastname: Lee
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Chang Gung Memorial Hospital, Chiayi, Taiwan jpgau@vghtpe.gov.tw chiachen.hsu1008@gmail.com.
authors.forename: Chia-Chen
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan jpgau@vghtpe.gov.tw chiachen.hsu1008@gmail.com.|Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taiwan.
authors.forename: Jyh-Pyng
authors.initials: JP
authors.lastname: Gau
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000235:genetics; D015415:Biomarkers; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D002881:Chromosomes, Human, Pair 12; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D056726:Genetic Association Studies; D025743:HMGA2 Protein / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology / Q000627:therapeutic use; D053614:Janus Kinase 2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D009196:Myeloproliferative Disorders / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D010641:Phenotype; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D014178:Translocation, Genetic
chemical_list: D015415:Biomarkers; D025743:HMGA2 Protein; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; C487931:mirnlet7 microRNA, human; D053614:Janus Kinase 2; D006918:Hydroxyurea