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GP130 activation induces myeloma and collaborates with MYC
Tobias Dechow, … , Florian Bassermann, Ulrich Keller
Tobias Dechow, … , Florian Bassermann, Ulrich Keller
Published November 10, 2014
Citation Information: J Clin Invest. 2014;124(12):5263-5274. https://doi.org/10.1172/JCI69094.
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Research Article Oncology

GP130 activation induces myeloma and collaborates with MYC

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Abstract

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.

Authors

Tobias Dechow, Sabine Steidle, Katharina S. Götze, Martina Rudelius, Kerstin Behnke, Konstanze Pechloff, Susanne Kratzat, Lars Bullinger, Falko Fend, Valeria Soberon, Nadya Mitova, Zhoulei Li, Markus Thaler, Jan Bauer, Elke Pietschmann, Corinna Albers, Rebekka Grundler, Marc Schmidt-Supprian, Jürgen Ruland, Christian Peschel, Justus Duyster, Stefan Rose-John, Florian Bassermann, Ulrich Keller

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Figure 1

Expression of activated STAT3 and STAT3 target genes is a hallmark of human MM.

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Expression of activated STAT3 and STAT3 target genes is a hallmark of hu...
(A–E) Immunohistochemical double staining of human BM biopsies for P-STAT3 (brown nuclear stain) and CD138 (red membrane stain). Original magnification, ×400. Plasma cells (arrowheads) in normal BM (A) and MGUS (B) were negative for P-STAT3, whereas positive endothelial cells were clearly visible. (C and E) MM biopsy with nuclear P-STAT3 positivity in the majority of tumor cells. (D) MM biopsy negative for P-STAT3. 2 positive endothelial cells (arrowheads) are illustrated as internal positive control. (F) Hierarchical cluster analysis of n = 304 human MM samples (GEO accession no. GSE26760) based on a STAT3 activation–associated gene expression signature (n = 67 genes; ref. 19). Group 2 correlated with high STAT3 expression (i.e., STAT3 activation). (G) GSEA showed a significantly different distribution of the STAT3 activation–associated genes, with group 1 being negatively correlated (NES, –1.97; P < 0.001).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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