title: Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B-cell receptor signaling and tumor growth in diffuse large B-cell lymphoma.
abstract: 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 whether the spatial organization of the BCR contributes to the 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.
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: D
authors: D
authors: Pore
authors: Department of Clinical Pathology, Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.
authors: J
authors: J
authors: Bodo
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: A
authors: A
authors: Danda
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: D
authors: D
authors: Yan
authors: Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.
authors: J G
authors: JG
authors: Phillips
authors: Department of Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA.
authors: D
authors: D
authors: Lindner
authors: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: B T
authors: BT
authors: Hill
authors: Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: M R
authors: MR
authors: Smith
authors: Department of Clinical Pathology, Institute of Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, USA.
authors: E D
authors: ED
authors: Hsi
authors: Department of Immunology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors: N
authors: N
authors: Gupta
mesh_terms: D000818:Animals; D017209:Apoptosis; D001706:Biopsy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008871:Microvilli / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D021381:Protein Transport; D015363:Quinolones / Q000494:pharmacology; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; C570897:NSC668394; D010636:Phenols; D015363:Quinolones; D011947:Receptors, Antigen, B-Cell; D014157:Transcription Factors