Tissue inhibitor of metalloproteinase 1 (TIMP-1) promotes plasmablastic differentiation of a Burkitt lymphoma cell line: implications in the pathogenesis of plasmacytic/plasmablastic tumors.
Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a stromal factor with multiple functions. Overexpression of TIMP-1 correlates with aggressive clinical behavior of a spectrum of tumors. Here, for the first time, we address the role of TIMP-1 in the pathogenesis of B-cell lymphomas. An Epstein-Barr virus (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 blotting. Analysis revealed 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 and up-regulated plasma cell-associated antigens CD138, MUM-1/IRF-4, XBP-1, and CD44, suggesting a plasma cell differentiation. This is accompanied by activation of signal transducer and activator of transcription 3 (STAT-3) 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.
Guedez
Liliana
L
Cell and Cancer Biology Branch and Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA. lquedezm@mail.nih.gov
Martinez
Antonio
A
Zhao
Shumei
S
Vivero
Angelica
A
Pittaluga
Stefania
S
Stetler-Stevenson
Maryalice
M
Raffeld
Mark
M
Stetler-Stevenson
William G
WG
D001402:B-Lymphocytes / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D002051:Burkitt Lymphoma / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015536:Down-Regulation / Q000235:genetics; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008221:Lymphoid Tissue / Q000201:enzymology / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009101:Multiple Myeloma / Q000201:enzymology / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010950:Plasma Cells / Q000473:pathology*; D012097:Repressor Proteins / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D014158:Transcription, Genetic / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics
D018797:Cell Cycle Proteins; D012097:Repressor Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D014157:Transcription Factors