Gene set enrichment analysis unveils the mechanism for the phosphodiesterase 4B control of glucocorticoid response in B-cell lymphoma.
Gene set enrichment analysis unveils the mechanism for the phosphodiesterase 4B control of glucocorticoid response in B-cell lymphoma.
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DOI：
10.1158/1078-0432.ccr-11-0770
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发表时间：
2011-11-01
期刊：
影响因子：
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通讯作者：
Aguiar RC
中科院分区：
文献类型：
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作者：
Kim SW;Rai D;Aguiar RC
对糖皮质激素（GC）的耐药是淋巴系统恶性肿瘤临床治疗中的一个重要问题。通过对相关信号通路的机械理解来解决这个问题更有可能产生积极的结果。我们使用基因集富集分析（GSEA），B细胞淋巴瘤细胞系中功能获得和丧失的多种遗传模型，体外和体内，以及主要患者样本来表征环AMP/磷酸二酯酶4 B（cAMP/PDE 4 B），AKT/ mTOR活性和GC反应之间的新关系。从GSEA开始，我们发现PDE 4 B在弥漫性大B细胞淋巴瘤（DLBCL）中的过表达影响在GC抗性肿瘤中异常活跃的相同基因/途径。我们使用遗传修饰的细胞系来显示PDE 4 B调节cAMP对AKT/mTOR通路的抑制活性，并定义DLBCL中的GC抗性。与这些数据一致，在人淋巴瘤异种移植模型中对PDE 4的药理学抑制释放了cAMP效应，抑制了AKT，并恢复了GC敏感性。最后，我们使用原发性DLBCL样本来确认PDE 4 B调节AKT/mTOR的临床相关性和生物标志物潜力。总之，这些数据从机制上阐明了cAMP如何调节淋巴细胞中的GC反应，将AKT定义为cAMP在B细胞中生长抑制作用的主要转导物，并允许制定基因组学指导的临床试验，以测试PDE 4抑制剂恢复GC敏感性和改善B细胞恶性肿瘤患者结局的能力。
Resistance to glucocorticoid (GC) is a significant problem in the clinical management of lymphoid malignancies. Addressing this issue via a mechanistic understanding of relevant signaling pathways is more likely to yield positive outcomes. We used gene set enrichment analysis (GSEA), multiple genetic models of gain and loss of function in B-cell lymphoma cell lines, in vitro and in vivo, and primary patient samples to characterize a novel relationship between the cyclic AMP/phosphodiesterase 4B (cAMP/PDE4B), AKT/ mTOR activities, and GC responses. Starting from the GSEA, we found that overexpression of the PDE4B in diffuse large B-cell lymphoma (DLBCL) impinge on the same genes/pathways that are abnormally active in GC-resistant tumors. We used genetically modified cell lines to show that PDE4B modulates cAMP inhibitory activities toward the AKT/mTOR pathway and defines GC resistance in DLBCL. In agreement with these data, pharmacologic inhibition of PDE4 in a xenograft model of human lymphoma unleashed cAMP effects, inhibited AKT, and restored GC sensitivity. Finally, we used primary DLBCL samples to confirm the clinical relevance and biomarker potential of AKT/mTOR regulation by PDE4B. Together, these data mechanistically elucidated how cAMP modulates GC responses in lymphocytes, defined AKT as the principal transducer of the growth inhibitory effects of cAMP in B cells, and allowed the formulation of genomics-guided clinical trials that test the ability of PDE4 inhibitors to restore GC sensitivity and improve the outcome of patients with B-cell malignancies.