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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

Leukemia volume 29, pages 1857–1867 (2015)Cite this article

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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.

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Acknowledgements

This study was funded by grants to NG (AI081743 from NIH and Cancer Research Institute Investigator Award). We thank Yvonne Parker for assistance with the animal experiments.

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Authors and Affiliations

  1. Department of Immunology, Lerner Research Institute,

    D Pore, A Danda, D Yan & N Gupta

  2. , Cleveland Clinic, Cleveland, OH, USA

    D Pore, A Danda, D Yan & N Gupta

  3. Department of Clinical Pathology, Institute of Pathology and Laboratory Medicine,

    J Bodo & E D Hsi

  4. , Cleveland Clinic, Cleveland, OH, USA

    J Bodo & E D Hsi

  5. Department of Translational Hematology and Oncology Research,

    J G Phillips & D Lindner

  6. , Cleveland Clinic, Cleveland, OH, USA

    J G Phillips & D Lindner

  7. Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA

    B T Hill & M R Smith

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Correspondence to N Gupta.

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Pore, D., Bodo, J., Danda, A. et al. Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B-cell receptor signaling and tumor growth in diffuse large B-cell lymphoma. Leukemia 29, 1857–1867 (2015). https://doi.org/10.1038/leu.2015.86

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