Dysregulation of the MIRLET7/HMGA2 axis with methylation of the CDKN2A promoter in myeloproliferative neoplasms. (19th September 2014)

• Record Type: Journal Article
• Authors: Harada‐Shirado, Kayo; Ikeda, Kazuhiko; Ogawa, Kazuei; Ohkawara, Hiroshi; Kimura, Hideo; Kai, Tatsuyuki; Noji, Hideyoshi; Morishita, Soji; Komatsu, Norio; Takeishi, Yasuchika
• Is Part Of: British journal of haematology. Volume 168:Number 3(2015:Feb.)
• Page Start: 338
• Page End: 349
• Publication Date: 2014-09-19
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.13129
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh13129-abs-0001"> <title>Summary</title> <p>Overexpression of <italic>high mobility group AT‐hook 2</italic> (<italic>Hmga2</italic>), which is negatively regulated by <italic>MIRLET7</italic> micro RNAs through 3′‐untranslated region (3′UTR), causes proliferative haematopoiesis mimicking myeloproliferative neoplasms (MPNs) and contributes to progression of myelofibrosis in mice. Thus, we investigated <italic>HMGA2 </italic>mRNA expression in 66 patients with MPNs including 23 polycythaemia vera (PV), 33 essential thrombocythaemia (ET) and 10 primary myelofibrosis (PMF). <italic>HMGA2 </italic>mRNA expression, especially variant 1 with 3′UTR that contains <italic>MIRLET7</italic>‐specific sites, rather than variant 2 lacking 3′UTR, is frequently deregulated due to decreased <italic>MIRLET7</italic> expression in granulocytes from over 20% of PV and ET, and in either granulocytes or CD34<sup>+</sup> cells from 100% of PMF. Patients with deregulated <italic>HMGA2 </italic>mRNA expression were significantly more likely to show splenomegaly, high serum lactate dehydrogenase values, and methylation of the <italic>CDKN2A</italic> promoter compared with other patients without deregulation of <italic>HMGA2</italic>. A histone deacetylase inhibitor, panobinostat, significantly increased <italic>MIRLET7</italic> expression and reduced variant 1 of <italic>HMGA2 </italic>mRNA expression, but not variant 2, in both U937 cells and PMF‐derived CD34<sup>+</sup> cells. Moreover, both panobinostat and small interfering RNA of <italic>HMGA2</italic> demethylated the <italic>CDKN2A</italic> promoter in U937 cells. In conclusion, the frequently dysregulated <italic>MIRLET7</italic>/<italic>HMGA2</italic> axis could be a therapeutic target in MPNs.</p> </abstract>