Two-phase culture in Diamond Blackfan anemia: localization of erythroid defect
Two-phase culture in Diamond Blackfan anemia: localization of erythroid defect
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DOI：
10.1182/blood-2004-03-1016
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发表时间：
2005-01-15
期刊：
影响因子：
20.3
通讯作者：
Ball, SE
中科院分区：
文献类型：
--
作者：
Ohene-Abuakwa, Y;Orfali, KA;Ball, SE
已知Diamond Blackfan贫血（DBA）中的红细胞缺陷是干细胞固有的，但其分子病理生理学仍不清楚。使用2相液体红细胞培养系统，我们已经证明了一致的缺陷DBA，无论临床严重程度，包括3个一级亲属与正常的血红蛋白水平，但增加红细胞腺苷脱氨酶活性。DBA培养物在无促红细胞生成素（Epo）阶段1结束前与对照组无区别，但在暴露于Epo时未能显示红细胞扩增和终末分化的正常同步波。在正常和DBA培养物中，地塞米松增加红系祖细胞的Epo敏感性，并增强2期红系扩增。在用地塞米松处理的DBA培养物中，Epo敏感性与正常相当，但红细胞扩增仍低于正常。在克隆形成2期文化中，正常文化和DBA之间的菌落数没有显着差异，在地塞米松的存在或不存在下，在低和高Epo浓度。然而，在所有条件下，DBA中的菌落明显较小。这表明Epo触发的终末成熟的起始在DBA中是完整的，并且缺陷位于Epo受体的下游，影响红系祖细胞的存活和/或增殖。(C)2005年美国血液学会。
The erythroid defect in Diamond Blackfan anemia (DBA) is known to be intrinsic to the stem cell, but its molecular pathophysiology remains obscure. Using a 2-phase liquid erythroid culture system, we have demonstrated a consistent defect in DBA, regardless of clinical severity, including 3 first-degree relatives with normal hemoglobin levels but increased erythrocyte adenosine deaminase activity. DBA cultures were indistinguishable from controls until the end of erythropoietin (Epo)-free phase 1, but failed to demonstrate the normal synchronized wave of erythroid expansion and terminal differentiation on exposure to Epo. Dexamethasone increased Epo sensitivity of erythroid progenitor cells, and enhanced erythroid expansion in phase 2 in both normal and DBA cultures. In DBA cultures treated with dexamethasone, Epo sensitivity was comparable to normal, but erythroid expansion remained subnormal. In clonogenic phase 2 cultures, the number of colonies did not significantly differ between normal cultures and DBA, in the presence or absence of dexamethasone, and at both low and high Epo concentrations. However, colonies were markedly smaller in DBA under all conditions. This suggests that the Epo-triggered onset of terminal maturation is intact in DBA, and the defect lies downstream of the Epo receptor, influencing survival and/or proliferation of erythroid progenitors. (C) 2005 by The American Society of Hematology.