miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets
miR-28 is a thrombopoietin receptor targeting microRNA detected in a fraction of myeloproliferative neoplasm patient platelets
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DOI：
10.1182/blood-2008-06-165985
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发表时间：
2010-07-22
期刊：
影响因子：
20.3
通讯作者：
Constantinescu, Stefan N.
中科院分区：
文献类型：
--
作者：
Girardot, Michael;Pecquet, Christian;Constantinescu, Stefan N.
BCR-ABL阴性骨髓增生性肿瘤（MPN;真性红细胞增多症，原发性血小板增多症，原发性骨髓纤维化）是由多能造血祖细胞引起的恶性疾病，通常由JAK 2 V617 F或其他JAK/STAT激活突变改变。血小板生成素受体（TpoR，MPL）是在骨髓谱系中使用JAK 2的主要二聚体细胞因子受体之一，并且发现在某些MPN患者中下调。我们寻找MPL表达的负调节因子。在这里，我们报告了miR-28靶向MPL的3'非翻译（3' UTR）区域，抑制其翻译，以及其他可能参与巨核细胞分化的蛋白质，如E2 F6。miR-28在CD 34来源的巨核细胞中的表达抑制终末分化。发现miR-28在一部分MPN患者的血小板中过表达，而在健康受试者的血小板中以恒定的低水平表达。STAT 5的组成性激活导致造血细胞系的自主生长与miR-28表达增加相关。我们讨论了如何下调MPL和其他目标的miR-28，相关的miR-708和miR-151，可能有助于MPN的致病性。（血。2010; 116（3）：437-445）
BCR-ABL negative myeloproliferative neoplasms (MPNs; polycythemia vera, essential thrombocythemia, primary myelofibrosis) are malignant diseases arising from a multipotent hematopoietic progenitor, frequently altered by JAK2 V617F or other JAK/STAT activating mutations. The thrombopoietin receptor (TpoR, MPL) is one of the major dimeric cytokine receptors that use JAK2 in the myeloid lineage, and was found to be down-modulated in certain MPN patients. We searched for negative regulators of MPL expression. Here we report that miR-28 targets the 3' untranslated (3'UTR) region of MPL, inhibiting its translation, as well as other proteins potentially involved in megakaryocyte differentiation, such as E2F6. Expression of miR-28 in CD34-derived megakaryocytes inhibited terminal differentiation. miR-28 was found to be overexpressed in platelets of a fraction of MPN patients, while it was expressed at constant low levels in platelets from healthy subjects. Constitutive activation of STAT5 leading to autonomous growth of hematopoietic cell lines was associated with increased miR-28 expression. We discuss how down-modulating MPL and other targets of miR-28, and of related miR-708 and miR-151, could contribute to MPN pathogenicity. (Blood. 2010; 116(3): 437-445)