Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926.
Self-renewal of acute lymphocytic leukemia cells is limited by the Hedgehog pathway inhibitors cyclopamine and IPI-926.
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DOI：
10.1371/journal.pone.0015262
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发表时间：
2010-12-28
期刊：
影响因子：
3.7
通讯作者：
Matsui W
中科院分区：
文献类型：
--
作者：
Lin TL;Wang QH;Brown P;Peacock C;Merchant AA;Brennan S;Jones E;McGovern K;Watkins DN;Sakamoto KM;Matsui W
保守的胚胎信号传导途径如Hedgehog（Hh）、Wingless和Notch已经涉及几种恶性肿瘤的发病机制。最近的数据表明，Hh信号在正常B细胞发育中起作用，我们假设Hh信号可能在前体B细胞急性淋巴细胞白血病（B-ALL）中很重要。我们发现Hh通路组分的表达在人B-ALL细胞系和临床样品中是常见的。此外，途径活性可以通过Hh配体或几种途径抑制剂（包括环巴胺和新型SMOOTHENED（SMO）抑制剂IPI-926）来调节。途径活性的抑制主要通过限制它们在体外和体内的自我更新潜力来影响表达醛脱氢酶（ALDH）的高度克隆形成性B-ALL细胞。这些数据表明，Hh通路激活在B-ALL中很常见，代表了一种调节恶性克隆自我更新和持久性的新治疗靶点。
Conserved embryonic signaling pathways such as Hedgehog (Hh), Wingless and Notch have been implicated in the pathogenesis of several malignancies. Recent data suggests that Hh signaling plays a role in normal B-cell development, and we hypothesized that Hh signaling may be important in precursor B-cell acute lymphocytic leukemia (B-ALL). We found that the expression of Hh pathway components was common in human B-ALL cell lines and clinical samples. Moreover, pathway activity could be modulated by Hh ligand or several pathway inhibitors including cyclopamine and the novel SMOOTHENED (SMO) inhibitor IPI-926. The inhibition of pathway activity primarily impacted highly clonogenic B-ALL cells expressing aldehyde dehydrogenase (ALDH) by limiting their self-renewal potential both in vitro and in vivo. These data demonstrate that Hh pathway activation is common in B-ALL and represents a novel therapeutic target regulating self-renewal and persistence of the malignant clone.
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