Aberrant let7a/HMGA2 signaling activity with unique clinical phenotype in <i>JAK2</i> -mutated myeloproliferative neoplasms

Abstract

High mobility group AT-hook 2 (HMGA2) is an architectural transcription factor that is negatively regulated by <i>let-7</i> microRNA through binding to it's 3'-untranslated region. Transgenic mice expressing <i>Hmga2</i> with a truncation of its 3'-untranslated region has been shown to exhibit a myeloproliferative phenotype. To decipher the <i>let-7-HMGA2</i> axis in myeloproliferative neoplasms, we employed an <i>in vitro</i> model supplemented with clinical correlation. Ba/F3 cells with inducible <i>JAK2</i>V617F expression (Ton.JAK2.V617F cells) showed upregulation of HMGA2 with concurrent <i>let-7a</i> repression. Ton.JAK2.V617F cells treated with a <i>let-7a</i> inhibitor exhibited further escalation of <i>Hmga2</i> expression, while a <i>let-7a</i> mimic diminished the <i>Hmga2</i> transcript level. <i>Hmga2</i> overexpression conferred <i>JAK2</i>-mutated cells with a survival advantage through inhibited apoptosis. A pan-JAK inhibitor, INC424, increased the expression of <i>let-7a</i>, downregulated the level of <i>Hmga2</i>, 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 <i>let-7a</i> and <i>HMGA2</i> Overexpression of <i>HMGA2</i> 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% <i>vs</i> 12.7%, <i>P</i>=0.044). Patients with upregulated <i>HMGA2</i> 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 <i>JAK2</i>, <i>MPL</i> and <i>CALR</i> Our findings suggest that, in a subset of myeloproliferative neoplasm patients, the <i>let-7-HMGA2</i> axis plays a prominent role in the pathogenesis of the disease that leads to unique clinical phenotypes.