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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.

SUBMITTER: Scherger AK

PROVIDER: S-EPMC6693839 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Scherger Anna K AK Al-Maarri Mona M Maurer H. Carlo HC Schick Markus M Maurer Sabine S Öllinger Rupert R Gonzalez-Menendez Irene I Martella Manuela M Thaler Markus M Pechloff Konstanze K Steiger Katja K Sander Sandrine S Ruland Jürgen J Rad Roland R Quintanilla-Martinez Leticia L Wunderlich Frank T FT Rose-John Stefan S Keller Ulrich U

JCI insight 20190808 15

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 inves ...[more]

PMID: 31391340

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Project description:BackgroundPeriodontitis is a major oral condition and current treatment outcomes can be unsatisfactory. Macrophages are essential to the regeneration process, so we investigated the influence of human dental pulp stem cells (hDPSCs) on macrophage differentiation and the microenvironment and the underlying mechanism.MethodshDPSCs were isolated from healthy third molars extracted from patients undergoing maxillofacial surgery. The surface antigens CD73, CD45, CD90 and CD11b of the hDPSCs were detected using flow cytometry. hDPSCs were induced for osteogenic and adipogenic differentiation, and the outcome was assessed by alizarin red staining or Oil Red O staining. The IL-6 level released by hDPSCs was measured by enzyme linked immunosorbent assay (ELISA). Tohoku Hospital Pediatrics-1 (THP-1) cells were cultured and induced into macrophages by phorbol-12-myristate-13-acetate. After coculture of THP-1-derived macrophages with hDPSCs, interleukin 6 (IL-6), Argininase-1 (Arg-1), Mannose receptor C-1 (Mrc-1), inducible nitric oxide synthase (iNOS), and tumor necrosis factor-α (TNF-α) levels in the medium were measured using ELISA and quantificational RT-PCR (qRT-PCR). The numbers of CD80+ and CD163+ macrophages were counted by immunofluorescence, and GP130/STAT3 signaling protein expression was detected. After coculturing the culture medium of hDPSCs with human bone marrow stem cells (BMSCs), scratch assays and transwell assays were performed to evaluate cell migration and invasion.ResultsAlkaline phosphatase (ALP) staining, alizarin red staining, and western blots were performed to assess osteoblast differentiation. The hDPSCs were positive for surface antigens CD73 and CD90 and negative for CD45 and CD11b expression. The level of IL-6 secreted by hDPSCs significantly increased the number of CD80+ cells as well as the levels of Arg-1 and Mrc-1. It also promoted M2 macrophage polarization and activated GP130/STAT3 signaling. However, the medium cocultured with THP-1-derived macrophages by hDPSCs facilitated the migration, invasion, and osteogenic abilities of human bone marrow-derived stem cells (hBMSCs).ConclusionshDPSCs can regulate the periodontal microenvironment through IL-6 by inducing phenotypic transformation of M2 macrophages and stimulating osteogenic differentiation of BMSCs.

Dataset Information

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

Publications

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

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