Activated gp130 signaling selectively targets B cell differentiation to induce mature lymphoma and plasmacytoma
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
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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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 2

Activated gp130 signaling promotes B cell differentiation and signaling associated with oncogenic pathways.

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Activated gp130 signaling promotes B cell differentiation and signaling ...
(A) Flow cytometry analysis of PB, spleen, and BM reveal a significant accumulation of mature IgD+ B cells within the ZsGreen+ population of CD19 L-gp mice while L-gp controls present with an immature IgM+ phenotype (n = 3). *P < 0.05, **P < 0.005, ***P < 0.0005, and ****P < 0.0001 as determined by 2-tailed Student’s t test. Shown are means ± SEM. (B) Heatmap depicting the expression of STAT3 target genes among various stages of B cell development. The upper part of the panel illustrates the respective cell type as well as results for mere STAT3 expression (third row from top) as opposed to STAT3 activity and IL-6/JAK/STAT3 pathway activity (top and second row from top, respectively) as determined by single-sample gene set enrichment analysis. (C) Volcano plot illustrating results from a differential gene expression analysis between CD19+ splenocytes isolated from WT and young CD19 L-gp mice. The top 15 up- (blue) and downregulated (red) genes are labeled. Positive log2 fold changes indicate higher levels in WT splenocytes. A total of 2094 differentially expressed genes (DEGs) were identified at an FDR ≤ 0.05. (D) PCA of RNA-Seq gene expression profiles obtained by isolating CD19+ splenocytes from WT (blue) and young CD19 L-gp (red) mice, respectively. (E) Heatmap depicting single-sample gene set enrichment results as normalized enrichment scores (NESs) for the indicated pathways and their distribution between CD19+ splenocytes isolated from WT (blue) and young CD19 L-gp (red) mice. All pathways shown are differentially enriched at an FDR < 0.1.