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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 1

In vivo model for conditional gp130 activation.

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In vivo model for conditional gp130 activation.
(A) Strategy to insert t...
(A) Strategy to insert the floxed L-gp130-2A-ZsGreen cassette under the control of the CAG promoter into the mouse ROSA26 locus. The targeted locus is depicted before and after homologous recombination. EcoRI sites within the targeted genomic region are indicated. Amp, ampicillin resistance gene; CAG, chicken–β-actin promoter with CMV–immediate early enhancer; DTA, diphtheria toxin fragment A; LAH, long arm of homology; L-gp130, leucine zipper plus glycoprotein 130; loxP, locus of recombination by Cre; neo, neomycin resistance gene; rox, locus of recombination by Dre; SAH, short arm of homology; SV-40, simian virus 40; WSS, Westphal stop sequence; ZsGreen, Zoanthus sp. green fluorescent protein. (B) Southern blot analysis of targeted embryonic stem cell clones. The EcoRI-PacI external probe was used to screen EcoRI-digested clonal DNA via Southern blot. Besides the 15.6-kb WT band, a 7.1-kb targeted band appeared in correctly targeted clones. To verify single integration, a radioactively labelled probe was removed from the Southern blot membrane, which was reprobed with internal neo probe showing a single 7.1-kb band in single integrated clones. Clone C6 was selected for generation of the L-gp130 mouse strain. (C) MEFs of indicated genotypes (symbols) were infected with the designated virus(es) and sorted for GFP/YFP positivity. Depicted is the mRNA expression for L-gp130 and gp130 relative to GAPDH. Shown are means ± SEM. (D) Immunoblot analysis of MEFs from C using the indicated antibodies. L-gp130 was detected using a gp130 antibody.

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