Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma
Anna K. Scherger, … , Stefan Rose-John, Ulrich Keller
Anna K. Scherger, … , Stefan Rose-John, Ulrich Keller
Published August 8, 2019
Citation Information: JCI Insight. 2019;4(15):e128435. https://doi.org/10.1172/jci.insight.128435.
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Research Article Oncology

Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma

Abstract

Aberrant activity of the glycoprotein 130 130/JAK/STAT3 (gp130/JAK/STAT3) signaling axis is a recurrent event in inflammation and cancer. In particular, it is associated with a wide range of hematological malignancies, including multiple myeloma and leukemia. Novel targeted therapies have only been successful for some subtypes of these malignancies, underlining the need for developing robust mouse models to better dissect the role of this pathway in specific tumorigenic processes. Here, we investigated the role of selective gp130/JAK/STAT3 activation by generating a conditional mouse model. This model targeted constitutively active, cell-autonomous gp130 activity to B cells, as well as to the entire hematopoietic system. We found that regardless of the timing of activation in B cells, constitutively active gp130 signaling resulted in the formation specifically of mature B cell lymphomas and plasma cell disorders with full penetrance, only with different latencies, where infiltrating CD138+ cells were a dominant feature in every tumor. Furthermore, constitutively active gp130 signaling in all adult hematopoietic cells also led to the development specifically of largely mature, aggressive B cell cancers, again with a high penetrance of CD138+ tumors. Importantly, gp130 activity abrogated the differentiation block induced by a B cell–targeted Myc transgene and resulted in a complete penetrance of the gp130-associated, CD138+, mature B cell lymphoma phenotype. Thus, gp130 signaling selectively provides a strong growth and differentiation advantage for mature B cells and directs lymphomagenesis specifically toward terminally differentiated B cell cancers.

Authors

Anna K. Scherger, Mona Al-Maarri, Hans Carlo Maurer, Markus Schick, Sabine Maurer, Rupert Öllinger, Irene Gonzalez-Menendez, Manuela Martella, Markus Thaler, Konstanze Pechloff, Katja Steiger, Sandrine Sander, Jürgen Ruland, Roland Rad, Leticia Quintanilla-Martinez, Frank T. Wunderlich, Stefan Rose-John, Ulrich Keller

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Figure 5

Activated gp130 abolishes the lymphoma phenotype of B cell–targeted Myc by enforcing plasmacytic differentiation.

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Activated gp130 abolishes the lymphoma phenotype of B cell–targeted Myc ...
(A) Schematic of the CD19 L-gp Myc fetal liver cell (FLC) transplantation. FLCs from triple-transgenic CD19 L-gp Myc embryos as well as from CD19 L-gp and Myc controls were isolated at day 13.5 of embryonic development. Then, 1.2 × 106 FLCs with 0.2 × 106 Ly5.1 BM support cells were transplanted into lethally irradiated C57BL/6 recipients. The mice were sacrificed upon disease onset and whole-body necropsy was performed. The data shown are from 1 representative experiment from a group size of n = 6 animals each. (B) Kaplan-Meier curve revealing a significantly shorter survival of mice transplanted with FLCs from CD19 L-gp Myc as compared with controls (n = 6 mice per group) (***P = 0.003, Mantel-Cox test). (C) Flow cytometric analysis of tumors. Tumors from CD19 L-gp Myc FLC–transplanted animals showed an accumulation of CD19−CD138+ PCs whereas this population was absent in CD19 L-gp and Myc control mice. At least 3 mice per genotype were analyzed. Shown are representative analyses. (D) Analysis of organ infiltration in CD19 L-gp Myc, CD19 L-gp, and Myc FLC–transplanted animals by distinct B cell populations as assessed by flow cytometry. Data are shown as mean percentage ± SEM assessed from at least 3 mice per genotype. *P < 0.05, **P < 0.005, ****P < 0.0001 by 2-way ANOVA test. (E) Histology and immunohistochemistry from nodal tumor material of 1 representative animal per group. CD19 L-gp Myc–transplanted mice showed high positivity for CD138 staining while lacking B220 expression, whereas CD138+ cells are completely absent in the Myc control. The highest Myc, Pax5, and Ki67 expression was seen in Myc controls. Depicted in the figures are results obtained from analysis of the inguinal and mesenteric LNs, respectively; 3 mice per genotype were analyzed. Original magnification, ×400.