P210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression
P210BCR-ABL inhibits SDF-1 chemotactic response via alteration of CXCR4 signaling and down-regulation of CXCR4 expression
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DOI：
10.1158/0008-5472.can-04-2152
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发表时间：
2005-04-01
期刊：
影响因子：
11.2
通讯作者：
Lonache, F
中科院分区：
文献类型：
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作者：
Geay, JF;Buet, D;Lonache, F
已经显示，p210（BCR-ABL）显著损害CXCR 4信号传导。我们在此报道，在急变期，对SDF-1的迁移反应发生了深刻的改变，而慢性期CD 34（+）细胞则正常地迁移到这种趋化因子。这种迁移缺陷与低CXCR 4膜表达有关。体外STI-571处理来自急变期患者的CD 34（+）细胞显著增加了CXCR 4转录和CXCR 4膜表达。由于p210（BCR-ABL）经常随着疾病进展而增加，我们确定了高和低p210（BCR-ABL）表达对粒细胞巨噬细胞集落刺激因子依赖性人细胞系MO 7 e中CXCR 4蛋白的影响。p210（BCR-ABL）表达通过两种不同的机制明显改变CXCR 4蛋白，这取决于其表达水平。在低表达时，检测到信号缺陷，而CXCR 4表达没有改变。然而，更高的p210（BCR-ABL）表达诱导CXCR 4显著下调，这与其转录降低有关。p210（BCR-ABL）的作用需要其酪氨酸激酶活性。总的来说，这些数据表明，p210（BCR-ABL）可以影响CXCR 4的一种以上的机制，并建议下调CXCR 4可能有重要意义的慢性粒细胞白血病的发病机制。
It has been shown that p210(BCR-ABL) significantly impairs CXCR4 signaling. We report here that the migratory response to SDF-1 was profoundly altered in blast crisis, whereas chronic-phase CD34(+) cells migrated normally to this chemokine. This migratory defect was associated with a low CXCR4 membrane expression. In vitro STI-571 treatment of CD34(+) cells from patients in blast crisis markedly increased the CXCR4 transcript and CXCR4 membrane expression. Because p210(BCR-ABL) frequently increases with disease progression, we determined the effects of high and low p210(BCR-ABL) expression on CXCR4 protein in the granulocyte macrophage colony-stimulating factor-dependent human cell line MO7e. p210(BCR-ABL) expression distinctly alters CXCR4 protein through two different mechanisms depending on its expression level. At low expression, a signaling defect was detected with no modification of CXCR4 expression. However, higher p210(BCR-ABL) expression induced a marked down-regulation of CXCR4 that is related to its decreased transcription. The effect of p210(BCR-ABL) required its tyrosine kinase activity. Collectively, these data indicate that p210(BCR-ABL) could affect CXCR4 by more than one mechanism and suggest that down-regulation of CXCR4 may have important implications in chronic myelogenous leukemia pathogenesis.