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The tumor suppressive TGF-β/SMAD1/S1PR2 signaling axis is recurrently inactivated in diffuse large B-cell lymphoma


Stelling, Anna; Hashwah, Hind; Bertram, Katrin; Manz, Markus G; Tzankov, Alexandar; Müller, Anne (2018). The tumor suppressive TGF-β/SMAD1/S1PR2 signaling axis is recurrently inactivated in diffuse large B-cell lymphoma. Blood, 131(20):2235-2246.

Abstract

The sphingosine-1-phosphate receptor S1PR2 and its downstream signaling pathway is commonly silenced in diffuse large B-cell lymphoma (DLBCL), either by mutational inactivation or through negative regulation by the oncogenic transcription factor FOXP1. In this study, we have examined the upstream regulators of S1PR2 expression and have newly identified the TGF-β/TGF-βR2/SMAD1 axis as critically involved in S1PR2 transcriptional activation. Phosphorylated SMAD1 directly binds to regulatory elements in the locus as assessed by chromatin immunoprecipitation, and the CRISPR-mediated genomic editing of , or in DLBCL cell lines renders cells unresponsive to TGF-β-induced apoptosis. DLBCL clones lacking any one of the three factors have a clear growth advantage in vitro, as well as in subcutaneous xenotransplantation models, and in a novel model of orthotopic growth of DLBCL cells in the spleens and bone marrow of MISTRG mice expressing various human cytokines. The loss of induces hyper-proliferation of the germinal center B-cell compartment of immunized mice and accelerates -driven lymphomagenesis in spontaneous and serial transplantation models. The specific loss of in murine GC B-cells phenocopies the effects of loss on GC B-cell hyper-proliferation. Finally, we show that SMAD1 expression is aberrantly downregulated in >85% of analyzed DLBCL patients. The combined results uncover an important novel tumor suppressive function of the TGF-β/TGF-βR2/SMAD1/S1PR2 axis in DLBCL, and show that DLBCL cells have evolved to inactivate the pathway at the level of SMAD1 expression.

Abstract

The sphingosine-1-phosphate receptor S1PR2 and its downstream signaling pathway is commonly silenced in diffuse large B-cell lymphoma (DLBCL), either by mutational inactivation or through negative regulation by the oncogenic transcription factor FOXP1. In this study, we have examined the upstream regulators of S1PR2 expression and have newly identified the TGF-β/TGF-βR2/SMAD1 axis as critically involved in S1PR2 transcriptional activation. Phosphorylated SMAD1 directly binds to regulatory elements in the locus as assessed by chromatin immunoprecipitation, and the CRISPR-mediated genomic editing of , or in DLBCL cell lines renders cells unresponsive to TGF-β-induced apoptosis. DLBCL clones lacking any one of the three factors have a clear growth advantage in vitro, as well as in subcutaneous xenotransplantation models, and in a novel model of orthotopic growth of DLBCL cells in the spleens and bone marrow of MISTRG mice expressing various human cytokines. The loss of induces hyper-proliferation of the germinal center B-cell compartment of immunized mice and accelerates -driven lymphomagenesis in spontaneous and serial transplantation models. The specific loss of in murine GC B-cells phenocopies the effects of loss on GC B-cell hyper-proliferation. Finally, we show that SMAD1 expression is aberrantly downregulated in >85% of analyzed DLBCL patients. The combined results uncover an important novel tumor suppressive function of the TGF-β/TGF-βR2/SMAD1/S1PR2 axis in DLBCL, and show that DLBCL cells have evolved to inactivate the pathway at the level of SMAD1 expression.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Hematology
04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:3 April 2018
Deposited On:12 Apr 2018 13:45
Last Modified:18 May 2018 01:03
Publisher:American Society of Hematology
ISSN:0006-4971
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1182/blood-2017-10-810630
PubMed ID:29615404

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