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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 Article has an altmetric score of 6

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 2

Plasma cell disorder with features of human myeloma.

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Plasma cell disorder with features of human myeloma.
(A) Top: Scheme of ...
(A) Top: Scheme of the retroviral expression plasmid used. Bottom: Transduction-transplantation model. 5-FU–mobilized donor BM (Balb/C) was infected with retrovirus and transplanted i.v. into lethally irradiated syngeneic recipients. (B) Survival analysis of lethally irradiated mice that received GFP (n = 15), WT GP130 (n = 17), or L-GP130 (n = 37) virus-infected BM grafts. Note that GFP and GP130 graft recipients did not succumb to GFP+ disease, but rather to other radiation-induced tumors or organ failure. (C) Representative images of mesenterial tumors that arose in primary L-GP130 BM graft recipients. 1 cm is shown for scale. (D) Histological and immunohistochemical analysis of a representative mesenterial tumor from a primary L-GP130 graft recipient. Kappa, Igκ light chain; Lambda, Igλ light chain. Original magnification, ×400. (E) Flow cytometric analysis of tumors from 3 L-GP130 mice. Contour blots are shown from gated viable lymphocytes. Numbers in the quadrants show percent cells rated negative or positive for the indicated antibody staining.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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