Fontenay-Roupie M, Bouscary D, Guesnu M, Picard F, Melle J, Lacombe C, Gisselbrecht S, Mayeux P, Dreyfus F
Département d'Hématologie, AP-HP, INSERM U363, Université René Descartes, Hôpital Cochin, Paris, France.
Br J Haematol. 1999 Aug;106(2):464-73. doi: 10.1046/j.1365-2141.1999.01539.x.
Ineffective erythropoiesis in myelodysplasia is characterized by a defect in erythroid progenitor growth and by abnormal erythroid differentiation. Increased apoptosis of erythroid, granulocytic and megakaryocytic lineages is thought to account for cytopenias. Erythropoietin (Epo)-induced BFU-E and CFU-E growth was studied in 25 myelodysplastic syndrome (MDS) marrow specimens and found to be drastically diminished. To investigate the functionality of Epo-R in MDS marrow, we focused on Epo-induced STAT5 activation. Epo was able to stimulate STAT5 DNA binding activity in all normal and 12/24 MDS marrows tested, with no correlation between the level of STAT5 activation and the development of erythroid colonies in response to Epo. In contrast, impaired proliferation of erythroid progenitors was related to an increased expression of the transmembrane mediator of apoptotic cell death Fas/CD95 on the glycophorin A+ subpopulation. Therefore we conclude that the stimulation of pro-apoptotic signals rather than the defect of anti-apoptotic pathways resulting from Epo-stimulated Jak2-STAT5 pathway, predominantly accounts for ineffective erythropoiesis in myelodysplasia.
骨髓增生异常综合征中无效红细胞生成的特征是红系祖细胞生长缺陷和红系分化异常。红系、粒系和巨核系细胞系凋亡增加被认为是血细胞减少的原因。在25份骨髓增生异常综合征（MDS）骨髓标本中研究了促红细胞生成素（Epo）诱导的爆式红系集落形成单位（BFU-E）和红系集落形成单位（CFU-E）的生长，发现其显著减少。为了研究MDS骨髓中Epo受体（Epo-R）的功能，我们重点关注Epo诱导的信号转导和转录激活因子5（STAT5）激活。在所有测试的正常骨髓和24份MDS骨髓中的12份中，Epo能够刺激STAT5的DNA结合活性，STAT5激活水平与Epo刺激后红系集落的形成之间无相关性。相反，红系祖细胞增殖受损与血型糖蛋白A+亚群上凋亡细胞死亡的跨膜介质Fas/CD95表达增加有关。因此我们得出结论，促凋亡信号的刺激而非Epo刺激的Jak2-STAT5途径导致的抗凋亡途径缺陷，主要是骨髓增生异常综合征中无效红细胞生成的原因。
