Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells
Constitutive activation of STAT5 and Bcl-xL overexpression can induce endogenous erythroid colony formation in human primary cells
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DOI：
10.1182/blood-2005-10-009514
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发表时间：
2006-09-01
期刊：
影响因子：
20.3
通讯作者：
Vainchenker, William
中科院分区：
文献类型：
--
作者：
Garcon, Loic;Rivat, Christine;Vainchenker, William
真性红细胞增多症 (PV) 的生物学标志是形成具有不依赖促红细胞生成素的分化的内源性红细胞集落 (EEC)。最近，研究表明 JAK2 (V617F) 的激活突变是 PV 的起源。在这项工作中，我们研究了 STAT5/Bcl-xL 通路是否负责 EEC 的形成。 STAT5 的组成型活性形式被转导到人红系祖细胞中，并诱导不依赖促红细胞生成素的终末分化和 EEC 形成。此外，尽管缺乏促红细胞生成素，但红系祖细胞中的 Bcl-xL 过度表达也能够诱导红系集落。相反，在 Epo 存在的情况下，人红细胞祖细胞中 siRNA 介导的 STAT5 和 Bcl-xL 敲除抑制了集落形成单位红细胞 (CFU-E) 的形成。总而言之，这些结果表明，持续水平的唯一 Bcl-xL 能够引起不依赖于 Epo 的红细胞集落形成，并表明在 PV 患者中，JAK2(V617F) 可能通过 STAT5/Bcl-xL 途径诱导 EEC。
The biologic hallmark of polycythemia vera (PV) is the formation of endogenous erythroid colonies (EECs) with an erythropoietin-independent differentiation. Recently, it has been shown that an activating mutation of JAK2 (V617F) was at the origin of PV. In this work, we studied whether the STAT5/Bcl-xL pathway could be responsible for EEC formation. A constitutively active form of STAT5 was transduced into human erythroid progenitors and induced an erythropoietin-independent terminal differentiation and EEC formation. Furthermore, Bcl-xL overexpression in erythroid progenitors was also able to induce erythroid colonies despite the absence of erythropoietin. Conversely, siRNA-mediated STAT5 and Bcl-xL knock-down in human erythroid progenitors inhibited colony-forming unit-erythroid (CFU-E) formation in the presence of Epo. Altogether, these results demonstrate that a sustained level of the sole Bcl-xL is capable of giving rise to Epo-independent erythroid colony formation and suggest that, in PV patients, JAK2(V617F) may induce EEC via the STAT5/Bcl-xL pathway.