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

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 7

Constitutive GP130 signaling collaborates with MYC to induce plasmacytoma and is responsible for the plasma cell phenotype.

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Constitutive GP130 signaling collaborates with MYC to induce plasmacytom...
(A) Eμ-Myc FLCs were infected with the indicated viruses and transplanted into lethally irradiated syngeneic mice. Recipients were then followed for disease onset. Median tumor latency was 19 days for L-GP130 and 54 days for GP130 (n = 5 mice per group). P < 0.05. (B) Flow cytometry to assess the percentage of GFP+ cells and GFP+B220+ B cells in BM, spleen (S), peripheral blood (PB), and lymph node (LN) of the indicated recipient mice. Pretumorous GP130 graft recipients (GP130pre) were included as a control. Bars represent mean ± SEM from n = 5 (GP130 and L-GP130) or n = 3 (GP130pre) mice. (C) Representative and (D) quantitative analysis of organ infiltration by GFP+B220–CD138+ cells in the indicated recipient mice. Bars represent mean ± SEM from n = 5 (GP130 and L-GP130) or n = 3 (GP130pre) mice. *P < 0.05. (E) Immunoblot analysis of BM B cells from the indicated recipient mice using the listed antibodies. (F) FISH for Myc aberrations in plasmacytomas of primary L-GP130 graft recipients. Shown are number and type of Myc aberrations and representative images (arrows indicate Myc aberrations). Original magnification, ×1,000.