The dominant negative β isoform of the glucocorticoid receptor is uniquely expressed in erythroid cells expanded from polycythemia vera patients.
The dominant negative β isoform of the glucocorticoid receptor is uniquely expressed in erythroid cells expanded from polycythemia vera patients.
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DOI：
10.1182/blood-2010-07-296921
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发表时间：
2011-07
期刊：
影响因子：
20.3
通讯作者：
L. Varricchio;E. Masselli;E. Alfani;A. Battistini;G. Migliaccio;A. Vannucchi;Wenyong Zhang;D. Rondelli;J. Godbold;B. Ghinassi;C. Whitsett;R. Hoffman;A. Migliaccio
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作者：
L. Varricchio;E. Masselli;E. Alfani;A. Battistini;G. Migliaccio;A. Vannucchi;Wenyong Zhang;D. Rondelli;J. Godbold;B. Ghinassi;C. Whitsett;R. Hoffman;A. Migliaccio
糖皮质激素受体(GR)激动剂在体内和体外均可促进红细胞生成。为了阐明显性阴性GRβ亚型(不能结合STAT-5)对红细胞生成的影响，对18例健康(非疾病)献血者和16例真性红细胞增多症(PV)患者的单个核细胞进行了红细胞扩增培养。GRβ在所有PV EBS中均有表达，但仅在第1天开始的EBS中表达。稳定GRβ基因的A3669G多态性在PV(55%；n=22；P=0.0028)和骨髓纤维化(35%；n=20)患者中的频率高于NDS(9%；n=22)或原发性血小板增多症(6%；n=15)。地塞米松对ND细胞的刺激增加了以低GATA1和β-珠蛋白表达为特征的未成熟EBs的数量，而PV培养产生了大量低水平GATA1和β-珠蛋白的未成熟EBs，而与地塞米松刺激无关。在ND EBS中，地塞米松和促红细胞生成素处理后，STAT-5不被磷酸化，也不与GRα形成转录活性复合体，而在PV EBS中，STAT-5被结构性磷酸化，但GRβ的表达阻止了GR/STAT-5复合体的形成。这些数据表明GRβ的表达和A3669G的存在可能参与了PV红细胞增多症的发生，并为新的治疗药物的鉴定提供了一个潜在的靶点。
Glucocorticoid receptor (GR) agonists increase erythropoiesis in vivo and in vitro. To clarify the effect of the dominant negative GRβ isoform (unable to bind STAT-5) on erythropoiesis, erythroblast (EB) expansion cultures of mononuclear cells from 18 healthy (nondiseased) donors (NDs) and 16 patients with polycythemia vera (PV) were studied. GRβ was expressed in all PV EBs but only in EBs from 1 ND. The A3669G polymorphism, which stabilizes GRβ mRNA, had greater frequency in PV (55%; n = 22; P = .0028) and myelofibrosis (35%; n = 20) patients than in NDs (9%; n = 22) or patients with essential thrombocythemia (6%; n = 15). Dexamethasone stimulation of ND cultures increased the number of immature EBs characterized by low GATA1 and β-globin expression, but PV cultures generated great numbers of immature EBs with low levels of GATA1 and β-globin irrespective of dexamethasone stimulation. In ND EBs, STAT-5 was not phosphorylated after dexamethasone and erythropoietin treatment and did not form transcriptionally active complexes with GRα, whereas in PV EBs, STAT-5 was constitutively phosphorylated, but the formation of GR/STAT-5 complexes was prevented by expression of GRβ. These data indicate that GRβ expression and the presence of A3669G likely contribute to development of erythrocytosis in PV and provide a potential target for identification of novel therapeutic agents.