Bock Oliver, Tessema Mathewos, Serinsöz Ebru, von Wasielewski Reinhard, Büsche Guntram, Kreipe Hans
Institute of Pathology, Medizinische Hochschule Hannover, Carl-Neuberg-Strasse 1, 30625, Germany.
Leuk Res. 2004 Nov;28(11):1145-51. doi: 10.1016/j.leukres.2004.03.009.
Philadelphia chromosome negative chronic myeloproliferative disorders (Ph- CMPD) comprise haematopoietic stem cell disorders with currently unknown underlying molecular defect. Insulin-like growth factor 2 (IGF-2) is an imprinted gene that is known to be involved in the regulation of normal cell growth and that is overexpressed by a variety of tumors. The expression of IGF-2 in bone marrow cells is largely unknown. In order to elucidate gene expression level, protein expression pattern, and a potential role of IGF-2 in the pathogenesis of Ph- CMPD, we quantitatively analyzed the expression of the IGF-2 gene in bone marrow cells of 69 cases with Ph- CMPD and 31 control cases by applying real-time RT-PCR. IGF-2 gene expression in idiopathic myelofibrosis (IMF) was significantly increased by up to 11-fold as compared to the control group (P < 0.0001). IMF also expressed higher IGF-2 gene level as compared to essential thrombocythaemia (ET) and polycythaemia vera (PV) (P < 0.0001, P = 0.005, respectively). Paranuclear IGF-2 protein could be demonstrated in IMF, ET, and PV exclusively in megakaryocytes and myeloid progenitor cells in contrast to undetectable IGF-2 protein in control cases. We conclude that overexpression of the IGF-2 gene is a pathogenic feature in IMF. In addition, an abundant translational and post-translational processing could explain the accumulation of IGF-2 protein detectable in all Ph- CMPD entities in contrast to non-neoplastic haematopoiesis. We conclude that IGF-2 represents a new molecular target for evaluation of underlying fundamental pathomechanisms in Ph- CMPD.
费城染色体阴性慢性骨髓增殖性疾病（Ph- CMPD）是造血干细胞疾病，目前其潜在分子缺陷尚不清楚。胰岛素样生长因子2（IGF-2）是一个印记基因，已知参与正常细胞生长的调节，并且在多种肿瘤中过表达。IGF-2在骨髓细胞中的表达情况 largely未知。为了阐明IGF-2的基因表达水平、蛋白表达模式及其在Ph- CMPD发病机制中的潜在作用，我们应用实时逆转录聚合酶链反应（RT-PCR）定量分析了69例Ph- CMPD患者和31例对照患者骨髓细胞中IGF-2基因的表达。与对照组相比，特发性骨髓纤维化（IMF）中IGF-2基因表达显著增加，高达11倍（P < 0.0001）。与原发性血小板增多症（ET）和真性红细胞增多症（PV）相比，IMF中IGF-2基因水平也更高（分别为P < 0.0001，P = 0.005）。与对照病例中未检测到IGF-2蛋白相反，在IMF、ET和PV中，仅在巨核细胞和髓系祖细胞中可证实有核旁IGF-2蛋白。我们得出结论，IGF-2基因的过表达是IMF的一个致病特征。此外，丰富的翻译和翻译后加工可以解释在所有Ph- CMPD实体中可检测到的IGF-2蛋白的积累，这与非肿瘤性造血形成对比。我们得出结论，IGF-2代表了评估Ph- CMPD潜在基本发病机制的一个新的分子靶点。
