Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia
Mechanisms and clinical significance of BIM phosphorylation in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2011-07-367417
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发表时间：
2012-02-16
期刊：
影响因子：
20.3
通讯作者：
Packham, Graham
中科院分区：
文献类型：
--
作者：
Paterson, Alex;Mockridge, C. Ian;Packham, Graham
B细胞受体和微环境来源的信号通过增加增殖和/或减少凋亡促进慢性淋巴细胞白血病（CLL）细胞的积累。在这项研究中，我们研究了BIM的调节，这是一种与BCL 2相关的促凋亡蛋白，它受到磷酸化的严格调节。表面IgM刺激增加了CLL样品亚组中2种BIM亚型BIMEL和BIML的磷酸化。相反，在正常B细胞中，抗IgM仅触发BIMEL的选择性磷酸化。在CLL中，抗IgM诱导的BIM磷酸化与未突变的IGHV基因状态和疾病进展相关。引人注目的是，它也与突变的IGHV基因亚群内的疾病进展有关。BIM磷酸化依赖于MEK 1/2激酶活性，我们确定BIMEL丝氨酸69，以前与促生存反应，作为CLL和拉莫斯细胞中磷酸化的主要位点。BIMEL/BIML磷酸化与促存活蛋白MCL 1的释放相关。CLL细胞与HK细胞的共培养（CLL微环境的模型）促进CLL细胞存活，并且与MEK 1/2活化和BIMEL磷酸化相关。因此，BIM磷酸化似乎在CLL细胞的凋亡调节中发挥关键作用，可能协调抗原和微环境来源的存活信号。抗原介导的BIM效应可能是临床行为的重要决定因素。（Blood.2012;119（7）：1726-1736）
B-cell receptor and microenvironment-derived signals promote accumulation of chronic lymphocytic leukemia (CLL) cells through increased proliferation and/or decreased apoptosis. In this study, we investigated the regulation of BIM, a proapoptotic BCL2-related protein, which is tightly regulated by phosphorylation. Surface IgM stimulation increased phosphorylation of 2 BIM isoforms, BIMEL and BIML, in a subset of CLL samples. In contrast, in normal B cells, anti-IgM triggered selective phosphorylation of BIMEL only. In CLL, anti-IgM-induced BIM phosphorylation correlated with unmutated IGHV gene status and with progressive disease. Strikingly, it was also associated with progressive disease within the mutated IGHV gene subset. BIM phosphorylation was dependent on MEK1/2 kinase activity, and we identified BIMEL serine 69, previously linked to pro-survival responses, as the major site of phosphorylation in CLL and in Ramos cells. BIMEL/BIML phosphorylation was associated with release of the pro-survival protein MCL1. Coculture of CLL cells with HK cells, a model of the CLL microenvironment, promoted CLL cell survival and was associated with MEK1/2 activation and BIMEL phosphorylation. Hence, BIM phosphorylation appears to play a key role in apoptosis regulation in CLL cells, potentially coordinating antigen and microenvironment-derived survival signals. Antigen-mediated effects on BIM may be an important determinant of clinical behavior. (Blood.2012;119(7):1726-1736)