GP130 activation induces myeloma and collaborates with MYC
| Autor: | Lars Bullinger, Nadya Mitova, Ulrich Keller, Christian Peschel, Katharina Götze, Jan Bauer, Stefan Rose-John, Tobias Dechow, Markus Thaler, Sabine Steidle, Corinna Albers, Falko Fend, Valeria Soberon, Martina Rudelius, Justus Duyster, Zhoulei Li, Susanne Kratzat, Elke Pietschmann, Florian Bassermann, Kerstin Behnke, Konstanze Pechloff, Marc Schmidt-Supprian, Jürgen Ruland, Rebekka Grundler |
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| Rok vydání: | 2014 |
| Předmět: |
Male
STAT3 Transcription Factor Plasma Cells Plasma cell Proto-Oncogene Proteins c-myc Pathogenesis Mice Cell Line Tumor Cytokine Receptor gp130 medicine Animals Humans STAT3 Multiple myeloma B cell Mice Inbred BALB C biology digestive oral and skin physiology Neoplasms Experimental General Medicine Plasma cell neoplasm medicine.disease medicine.anatomical_structure biology.protein Cancer research Female Ectopic expression Signal transduction Multiple Myeloma Research Article Signal Transduction |
| Zdroj: | Journal of Clinical Investigation. 124:5263-5274 |
| ISSN: | 0021-9738 |
| DOI: | 10.1172/jci69094 |
| Popis: | Multiple myeloma (MM) is a plasma cell neoplasm that results from clonal expansion of an Ig-secreting terminally differentiated B cell. Advanced MM is characterized by tissue damage that involves bone, kidney, and other organs and is typically associated with recurrent genetic abnormalities. IL-6 signaling via the IL-6 signal transducer GP130 has been implicated as an important driver of MM pathogenesis. Here, we demonstrated that ectopic expression of constitutively active GP130 (L-GP130) in a murine retroviral transduction-transplantation model induces rapid MM development of high penetrance. L-GP130-expressing mice recapitulated all of the characteristics of human disease, including monoclonal gammopathy, BM infiltration with lytic bone lesions, and protein deposition in the kidney. Moreover, the disease was easily transplantable and allowed different therapeutic options to be evaluated in vitro and in vivo. Using this model, we determined that GP130 signaling collaborated with MYC to induce MM and was responsible and sufficient for directing the plasma cell phenotype. Accordingly, we identified Myc aberrations in the L-GP130 MM model. Evaluation of human MM samples revealed recurrent activation of STAT3, a downstream target of GP130 signaling. Together, our results indicate that deregulated GP130 activity contributes to MM pathogenesis and that pathways downstream of GP130 activity have potential as therapeutic targets in MM. |
| Databáze: | OpenAIRE |
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