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Lymphoma

TGFβ-mediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cell proliferation

Leukemia volume 18, pages 2015–2025 (2004)Cite this article

Abstract

We have previously reported an overexpression of Smad1 in follicular lymphoma (FL) cells, which are characterized by the t(14;18) bcl2/IgH translocation. Smad1 is commonly involved in bone morphogenetic protein but not in tumor-transforming growth factor beta (TGFβ) signaling pathways. This study focuses on Smad1 signaling pathway in non-Hodgkin lymphoma cells including follicular or large-cell lymphoma cells. Our results support the notion that phosphorylation of Smad1 is mediated by TGFβ present in the microenvironment and occurs in FL in vivo. Using an in vitro coculture system mimicking interactions between stroma cells and FL cells, we found that both the cell partners release TGFβ at a sufficient concentration to activate Smad pathways in the malignant cells. This Smad1 activation involves TGFβRII but not ALK-1 receptors, and does not compete with the Smad2 pathway. Moreover, proliferation assays performed on lymphoma cells expressing wild-type or mutated Smad1, or in which endogenous Smad1 level was decreased by gene silencing, strongly supported that overexpression and activation of Smad1 modifies the biological response of lymphoma B cells to TGFβ family members. This work opens new insights into aberrant Smad pathways and their pathophysiological role in FL and in other non-Hodgkin lymphomas.

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Acknowledgements

We are very grateful to Dr Teru Hideshima for his expertise in preparation of BMSCs and Dr F Pouliot for providing the Smad1-wt and Smad1-mut constructs. We are very grateful to Mrs S Lazo-Kallanian for excellent technical assistance in cell sorting by cytometry. We also thank Dr M Shipp, Dr LD Mayer, Dr AL Epstein and Dr T Denyssevych who kindly provided us with cell lines. We also appreciate Dr V Boussiotis for very helpful discussions. This work was supported by the Leukemia and Lymphoma Society of America, The Goldfine Family Lymphoma Research Fund and partly by the Wilhelm Sander-Stiftung (Grant 2000/022.1), Germany to FF.

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  1. H Husson

    Present address: Genzyme Corporation, Framingham, MA, USA

Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    O Munoz, R de Beaumont, H Husson, A Astier & A S Freedman

  2. Department of Medicine, Harvard Medical School, Boston, MA, USA

    O Munoz, A Astier & A S Freedman

  3. Institute of Pathology, Technical University Munich, Munich, Germany

    F Fend

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Correspondence to O Munoz or A S Freedman.

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Munoz, O., Fend, F., de Beaumont, R. et al. TGFβ-mediated activation of Smad1 in B-cell non-Hodgkin's lymphoma and effect on cell proliferation. Leukemia 18, 2015–2025 (2004). https://doi.org/10.1038/sj.leu.2403485

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