Decreased expression level of SH2 domain-containing protein tyrosine phosphatase-I (ShpI) is associated with progression of chronic myeloid leukaemia
Decreased expression level of SH2 domain-containing protein tyrosine phosphatase-I (ShpI) is associated with progression of chronic myeloid leukaemia
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DOI：
10.1002/path.2178
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发表时间：
2007-08-01
影响因子：
7.3
通讯作者：
Garcia-Manero, G.
中科院分区：
文献类型：
--
作者：
Amin, H. M.;Hoshino, K.;Garcia-Manero, G.
慢性粒细胞白血病（CML）的特征是t（9;22）（q34;q11）和融合蛋白Bcr-Abl的异常表达，其导致c-Abl激酶的组成性激活。Bcr-Abl在慢性、加速和急变期CML的发生和进展中起主要作用。Bcr-Abl和其他致癌分子之间的相互作用已被广泛记录。尽管如此，Bcr-Abl的负调节机制尚未完全确定。一种主要的抑制途径是通过含有SH 2结构域的蛋白酪氨酸磷酸酶Shp 1介导的。在本研究中，我们证明，晚期CML患者与慢性期患者相比，Shp 1水平显著降低。这一过程与DNA甲基化无关。此外，我们在CML细胞系或患者样本中未检测到Shp 1基因突变。这些数据表明，晚期CML患者中Shpl的减少是由于转录后修饰。我们的研究结果表明，Shp 1表达水平的降低在CML的进展中起着重要作用。此外，Shpl的减少及其随后对Bcr-Abl的抑制作用可以解释晚期CML患者中观察到的伊马替尼耐药。版权所有（C）2007大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
Chronic myeloid leukaemia (CML) is characterized by t(9;22)(q34;q11) and the aberrant expression of the fusion protein Bcr-Abl that leads to constitutive activation of c-Abl kinase. Bcr-Abl plays a major role in the development and progression of CML through chronic, accelerated, and blast phases. The interaction between Bcr-Abl and other oncogenic molecules has been extensively documented. Nonetheless, negative regulatory mechanisms of Bcr-Abl are not completely defined. One major inhibitory pathway is mediated via the SH2 domain-containing protein tyrosine phosphatase Shp1. In the present study, we demonstrate that Shp1 levels are markedly decreased in advanced stage CML patients compared with those in chronic phase. This process was independent of DNA methylation. Furthermore, we did not detect mutations in the Shp1 gene in CML cell lines or patient samples. These data suggest that the decrease in Shpl in advanced stage CML patients is due to posttranscriptional modifications. Our findings suggest that the decrease in Shp1 expression levels plays a role in the progression of CML. Also, the decrease in Shpl and subsequently its inhibitory effect on Bcr-Abl could provide an explanation for imatinib resistance seen in advanced stage CML patients. Copyright (C) 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.