Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-Cell lymphoma cell lines to CD40-mediated cell death
Constitutive activation of extracellular signal-regulated kinase predisposes diffuse large B-Cell lymphoma cell lines to CD40-mediated cell death
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DOI：
10.1158/0008-5472.can-05-2498
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发表时间：
2006-04-01
期刊：
影响因子：
11.2
通讯作者：
Sladek, R
中科院分区：
文献类型：
--
作者：
Hollmann, CA;Owens, T;Sladek, R
CD40促进正常B细胞的存活、增殖和分化，但可导致恶性淋巴细胞中活化诱导的细胞死亡。CD40配体和抗CD40抗体已成功地用于在体外和异种移植肿瘤模型中诱导淋巴瘤细胞系的凋亡。虽然这使得CD40成为抗肿瘤治疗的有吸引力的靶点，但恶性11细胞对CD40信号传导的反应是可变的，并且CD40刺激可以增强增殖并可以增加某些细胞系的化学抗性。因此，鉴定预测特定细胞系或肿瘤在用CD40刺激时是否将经历凋亡的标记物以及鉴定仅影响CD40信号传导的凋亡臂的CD40下游的靶标将是有用的。我们分析了CD40敏感和D40耐药的弥漫性大B细胞淋巴瘤（DLBCL）细胞系的基因表达模式，以确定参与CD40介导的细胞凋亡的信号通路。CD40耐药细胞系表达前B细胞标志物，包括RAG和VPRE B，而CD40敏感细胞类似于成熟的B细胞，并表达更高水平的编码CD40信号通路几个成员的转录本，包括LCK和VAV。此外，CD40敏感的DLBCL细胞系也显示出细胞外信号调节激酶（ERK）的组成性激活，并且当ERK磷酸化被抑制时不能进行凋亡。与此相反，CD40抗性系显示ERK无组成性激活，并且响应于CD40刺激ERK活性无增加。我们的研究结果表明，ERK的组成性激活可能需要通过CD40的死亡信号。
CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant 13 lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant 11 cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and D40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40.