Bcr-Abl induces autocrine IGF-1 signaling
Bcr-Abl induces autocrine IGF-1 signaling
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DOI：
10.1038/onc.2008.8
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发表时间：
2008-06-19
期刊：
影响因子：
8
通讯作者：
Geyer, C. R.
中科院分区：
文献类型：
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作者：
Lakshmikuttyamma, A.;Pastural, E.;Geyer, C. R.
Bcr-Abl癌基因是慢性粒细胞白血病（CML）的始发基因，Bcr-Abl抑制剂伊马替尼可有效治疗CML。随着时间的推移，患者对治疗产生耐药性，并进展为爆炸危机，这是一种由额外的遗传和表观遗传畸变驱动的事件。最近，我们发现Riz 1的表达在急变期减少，Riz 1的重新表达抑制IGF-1的表达。IGF-1信号在造血的许多阶段都是必需的，自分泌IGF-1信号的不适当激活可能会促进转化为急变。我们观察到，在11例匹配的CML患者活检中，有8例在原始细胞危象中IGF-1表达升高。我们研究了CML急变细胞系激活IGF-1表达的机制。我们发现Bcr-Abl使用Hck和Stat 5 b激活自分泌IGF- 1信号传导。使用小分子药物或shRNA抑制这些信号传导组分会降低增殖并增强凋亡。总之，我们的研究表明，异常的IGF- 1信号是一个重要的事件，在急变转化，它提供了一种机制来解释IGF-1 R和HCK抑制剂的活性，在阻止CML急变表型。
Bcr-Abl oncogene is responsible for the initial phase of chronic myelogenous leukemia (CML), which is effectively treated by the Bcr-Abl inhibitor imatinib. Over time patients become resistant to treatment and progress to blast crisis, an event that is driven by additional genetic and epigenetic aberrations. Recently, we showed that Riz1 expression decreases in blast crisis and that re-expression of Riz1 inhibits IGF-1 expression. IGF-1 signaling is required in many stages of hematopoiesis and inappropriate activation of autocrine IGF-1 signaling may facilitate transformation to blast crisis. We observed that in 8 out of 11 matched CML patient biopsies the IGF-1 expression is elevated in blast crisis. We examined mechanisms used by CML blast crisis cell lines to activate IGF-1 expression. We found that Bcr-Abl activates autocrine IGF- 1 signaling using Hck and Stat5b. Inhibition of these signaling components using small molecule drugs or shRNA decreases proliferation and enhances apoptosis. Together, our study suggests that aberrant IGF- 1 signaling is an important event in blast crisis transformation and it provides a mechanism to explain the activity of IGF-1R and Hck inhibitors in blocking CML blast crisis phenotypes.