Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in -mutated myeloproliferative neoplasms.

High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by microRNA through binding to it's 3'-untranslated region. Transgenic mice expressing with a truncation of its 3'-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the axis in myeloproliferative neoplasms, we employed an model supplemented with clinical correlation. Ba/F3 cells with inducible V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent repression. Ton.JAK2.V617F cells treated with a inhibitor exhibited further escalation of expression, while a mimic diminished the transcript level. overexpression conferred -mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of , downregulated the level of , 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 and Overexpression of 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% 12.7%, =0.044). Patients with upregulated 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 , and Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.