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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

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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 6

Conditional gp130 activation in hematopoietic stem/progenitor cells results in a highly aggressive B cell malignancy.

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Conditional gp130 activation in hematopoietic stem/progenitor cells resu...
(A) Kaplan-Meier curve showing survival of Vav1 L-gp mice (n = 44) in comparison with Vav1 (n = 26) and L-gp (n = 33) controls. Vav1 L-gp compound mice had a median survival of 53 days. Controls did not show any signs of malignancy within the observed time frame (****P < 0.0001, Mantel-Cox test). (B) WBC analysis of PB in diseased Vav1 L-gp mice (n = 27) in comparison with normal Vav1 (n = 5) and L-gp (n = 6) controls (*P < 0.05, 2-tailed Student’s t test). Shown are means ± SEM. (C) Flow cytometric analysis of diseased Vav1 L-gp mice (n = 11 analyzed) for distinct B cell subsets. Cells were gated for PI−ZsGreen+ living cells. Shown is the LN sample of 1 representative animal. Pro-/pre- and immature B cells (left) were present, while a small fraction of CD138+ PCs was seen (middle). The CD19+ B cell population was identified as a mature IgD+ differentiation state (right). (D) Quantitative analysis of LN infiltration by the distinct B cell subsets as shown in C from n = 11 mice. Bars represent the mean percentage ± SEM. The previous gate was set on ZsGreen+ living cells. (E) Quantitative analysis of LN infiltration by the distinct B cell subsets as shown in C from n = 11 mice. Bars represent the mean percentage ± SEM. The previous gate was on ZsGreen+ living B cells. (F) Histological and immunohistochemical analysis from spleen (left) and LN (right) of a representative diseased Vav1 L-gp mouse. H&E staining revealed high infiltration of tumor cells into both organs (upper row). The lower rows show B220+ and CD138+ expression; 11 mice were analyzed. Original magnification, ×400.

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