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Blood, 15 February 2005, Vol. 105, No. 4, pp. 1660-1668.
Prepublished online as a Blood First Edition Paper on October 12, 2004; DOI 10.1182/blood-2004-04-1385.
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Submitted April 12, 2004
Accepted September 30, 2004
Tissue inhibitor of metalloprotease(TIMP)-1 promotes plasmablastic differentiation of a Burkitt lymphoma cell line: implications in the pathogenesis of plasmacytic/plasmablastic tumors
Liliana Guedez*, Antonio Martinez, Shumei Zhao, Angelica Vivero, Stefania Pittaluga, Maryalice Stetler-Stevenson, Mark Raffeld, and William G Stetler-Stevenson
Cell and Cancer Biology, National Cancer Institute, Bethesda, MD, USA
Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA; Department of Pathology, Hospital del Mar, Barcelona, Spain
Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA
* Corresponding author; email: Lquedezm{at}mail.nih.gov.
Tissue inhibitor of metalloprotease(TIMP)-1 is a stromal factor with multiple functions. TIMP-1 overexpression correlates with aggressive clinical behavior of a spectrum of tumors. Here, for the first time, we addressed the role of TIMP-1 in the pathogenesis of B-cell lymphomas. An EBV-negative Burkitt lymphoma cell line with ectopic TIMP-1 expression (TIMP-1JD38) was used to identify genes induced/repressed by TIMP-1. Differentially expressed genes were analyzed by cDNA microarray, and they were validated by immunohistochemistry, flow cytometry, and Western blot. Analysis reveals changes of genes coding for B-cell growth/differentiation, transcription, and cell cycle regulators. TIMP-1 repressed expression of germinal-center(GC) markers CD10, Bcl-6, PAX-5, upregulated plasma cell associated antigens CD138, MUM-1/IRF-4, XBP-1, and CD44, suggesting a plasma-cell differentiation. This is accompanied by Stat-3 activation and switch to Cyclin D2 expression. However, TIMP-1JD38 cells expressed an inactive form of XBP-1, lacking antibody production/secretion. This incomplete plasmacytic differentiation occurs without altering cell proliferation, and despite c-Myc deregulation, indicating an arrested plasmacytic/plasmablastic stage of differentiation. Further validation in human-lymphoma cell lines and in primary B-cell tumors demonstrated a predominant TIMP-1 expression in tumors with plasmacytic/plasmablastic phenotypes, including multiple myelomas. These findings strongly support TIMP-1 as an important factor in the pathogenesis of plasmacytic/plasmablastic tumors.
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