Kogawa K, Mogi Y, Morii K, Takimoto R, Niitsu Y
Department of Internal Medicine, Sapporo Medical University.
Rinsho Ketsueki. 1994 Apr;35(4):370-5.
In the present paper, we investigated the pathophysiological implication of TGF-beta from megakaryocytes or megakaryoblasts in the development of myelofibrosis. In the bone marrow of myelofibrosis, proliferation of megakaryocytes is often noticed. We therefore investigated the TGF-beta expression in the bone marrow megakaryocytes from 12 chronic myeloproliferative disorder patients with myelofibrosis by immunohistochemical analysis. About all the specimen showed strong positivity for TGF-beta. In order to examine whether megakaryoblasts produce TGF-beta, we then measured TGF-beta activity in the conditioned medium (CM) of megakaryoblasts from a patient with acute megakaryoblastic leukemia who had profound myelofibrosis. The CM showed strong collagen synthesis stimulating activity which was nullified by addition of anti TGF-beta antibody. Since TGF-beta exists as latent form in platelets, TGF-beta was considered to be altered from active to latent form during megakaryocytes differentiation. In this context, MEG-01, a megakaryoblastic cell line which produces active TGF-beta was underwent differentiation to produce platelet-like bleb with TPA treatment. During the differentiation, MEG-01 showed the decrease of active TGF-beta production and increase of latent TGF-beta together with the production of LTBP. These results suggest that megakaryoblasts produce active TGF-beta and may may cause myelofibrosis, while more differentiated megakaryocytes produce latent TGF-beta. Mechanism by which megakaryoblast escape from negative autocrine of active TGF-beta was also investigated. MEG-01 was found to express mutated p53 which is considered to be responsible for impaired signal transduction of TGF-beta.
在本论文中，我们研究了巨核细胞或巨核母细胞来源的转化生长因子-β（TGF-β）在骨髓纤维化发展过程中的病理生理意义。在骨髓纤维化患者的骨髓中，常可观察到巨核细胞的增殖。因此，我们通过免疫组织化学分析，研究了12例慢性骨髓增殖性疾病伴骨髓纤维化患者骨髓巨核细胞中TGF-β的表达情况。几乎所有标本的TGF-β均呈强阳性。为了检测巨核母细胞是否产生TGF-β，我们随后检测了一名患有严重骨髓纤维化的急性巨核细胞白血病患者的巨核母细胞条件培养基（CM）中的TGF-β活性。该CM显示出强烈的胶原合成刺激活性，加入抗TGF-β抗体后该活性消失。由于TGF-β以潜伏形式存在于血小板中，因此认为TGF-β在巨核细胞分化过程中从活性形式转变为潜伏形式。在此背景下，用佛波酯（TPA）处理能产生活性TGF-β的巨核母细胞系MEG-01，使其分化产生血小板样小泡。在分化过程中，MEG-01活性TGF-β的产生减少，潜伏TGF-β及潜伏TGF-β结合蛋白（LTBP）的产生增加。这些结果表明，巨核母细胞产生活性TGF-β，可能导致骨髓纤维化，而分化程度更高的巨核细胞产生潜伏TGF-β。我们还研究了巨核母细胞逃避活性TGF-β负性自分泌的机制。发现MEG-01表达突变型p53，这被认为是TGF-β信号转导受损的原因。
