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Dysregulation of the MIRLET 7 / HMGA 2 axis with methylation of the CDKN 2A promoter in myeloproliferative neoplasms
Author(s) -
HaradaShirado Kayo,
Ikeda Kazuhiko,
Ogawa Kazuei,
Ohkawara Hiroshi,
Kimura Hideo,
Kai Tatsuyuki,
Noji Hideyoshi,
Morishita Soji,
Komatsu Norio,
Takeishi Yasuchika
Publication year - 2015
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13129
Subject(s) - methylation , microbiology and biotechnology , cancer research , biology , chemistry , genetics , gene
Summary Overexpression of high mobility group AT‐hook 2 ( Hmga2 ), which is negatively regulated by MIRLET7 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 HMGA2 mRNA expression in 66 patients with MPNs including 23 polycythaemia vera (PV), 33 essential thrombocythaemia (ET) and 10 primary myelofibrosis (PMF). HMGA2 mRNA expression, especially variant 1 with 3′UTR that contains MIRLET7 ‐specific sites, rather than variant 2 lacking 3′UTR, is frequently deregulated due to decreased MIRLET7 expression in granulocytes from over 20% of PV and ET, and in either granulocytes or CD34 + cells from 100% of PMF. Patients with deregulated HMGA2 mRNA expression were significantly more likely to show splenomegaly, high serum lactate dehydrogenase values, and methylation of the CDKN2A promoter compared with other patients without deregulation of HMGA2 . A histone deacetylase inhibitor, panobinostat, significantly increased MIRLET7 expression and reduced variant 1 of HMGA2 mRNA expression, but not variant 2, in both U937 cells and PMF‐derived CD34 + cells. Moreover, both panobinostat and small interfering RNA of HMGA2 demethylated the CDKN2A promoter in U937 cells. In conclusion, the frequently dysregulated MIRLET7 / HMGA2 axis could be a therapeutic target in MPNs.