Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B-cell receptor signaling and tumor growth in diffuse large B-cell lymphoma.
Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B-cell receptor signaling and tumor growth in diffuse large B-cell lymphoma.
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DOI：
10.1038/leu.2015.86
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发表时间：
2015-09
期刊：
影响因子：
11.4
通讯作者：
Gupta N
中科院分区：
文献类型：
--
作者：
Pore D;Bodo J;Danda A;Yan D;Phillips JG;Lindner D;Hill BT;Smith MR;Hsi ED;Gupta N
弥漫性大B细胞淋巴瘤（DLBCL）是一种与侵袭性临床病程相关的血液癌症。DLBCL的主要亚型显示慢性或紧张性B细胞抗原受体（BCR）信号传导的特征。然而，目前尚不清楚BCR的空间组织是否有助于调节促生存信号通路和细胞生长。在这里，我们表明，原发性DLBCL肿瘤和患者来源的DLBCL细胞系含有高水平的磷酸化Ezrin-Radixin-Moesin（ERM）蛋白。活化B细胞和生发B细胞亚型DLBCL细胞中的表面BCR与磷酸化ERM共分离，表明细胞骨架网络可能支持局部BCR信号传导并促进发病。事实上，显性失活突变体的膜-细胞骨架连接的消融、ERM蛋白的药理学抑制和敲低破坏了细胞表面BCR组织，抑制了近端和远端BCR信号传导，并降低了DLBCL细胞系的生长。ezrin抑制剂的体内施用延缓DLBCL肿瘤异种移植物的生长，伴随着肿瘤内磷酸化ERM水平的降低，抑制促存活信号传导和细胞凋亡的诱导。我们的结果揭示了一种新型的基于ERM的空间机制，该机制被DLBCL细胞利用来维持肿瘤细胞的生长和生存。
Diffuse large B cell lymphoma (DLBCL) is a hematological cancer associated with an aggressive clinical course. The predominant subtypes of DLBCL display features of chronic or tonic B cell antigen receptor (BCR) signaling. However, it is not known if the spatial organization of the BCR contributes to regulation of pro-survival signaling pathways and cell growth. Here, we show that primary DLBCL tumors and patient-derived DLBCL cell lines contain high levels of phosphorylated Ezrin-Radixin-Moesin (ERM) proteins. The surface BCRs in both activated B cell and germinal B cell subtype DLBCL cells co-segregate with phosphoERM suggesting that the cytoskeletal network may support localized BCR signaling and contribute to pathogenesis. Indeed, ablation of membrane-cytoskeletal linkages by dominant negative mutants, pharmacological inhibition and knockdown of ERM proteins disrupted cell surface BCR organization, inhibited proximal and distal BCR signaling, and reduced the growth of DLBCL cell lines. In vivo administration of the ezrin inhibitor retarded the growth of DLBCL tumor xenografts, concomitant with reduction in intratumor phosphoERM levels, dampened pro-survival signaling and induction of apoptosis. Our results reveal a novel ERM-based spatial mechanism that is coopted by DLBCL cells to sustain tumor cell growth and survival.