1. Role of leukemia cell invadosome in extramedullary infiltration.
- Author
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Stefanidakis M, Karjalainen K, Jaalouk DE, Gahmberg CG, O'Brien S, Pasqualini R, Arap W, and Koivunen E
- Subjects
- Animals, CD18 Antigens genetics, CD18 Antigens metabolism, Cell Adhesion, Cell Line, Tumor, Cell Movement, Cell Proliferation, Enzyme Precursors genetics, Enzyme Precursors metabolism, Flow Cytometry, Fluorescent Antibody Technique, Humans, Immunoblotting, Leukemia, Myeloid, Acute metabolism, Matrix Metalloproteinase 9 genetics, Matrix Metalloproteinase 9 metabolism, Mice, Mice, Inbred BALB C, Mice, Nude, RNA, Messenger genetics, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Xenograft Model Antitumor Assays, Enzyme Precursors antagonists & inhibitors, Leukemia, Myeloid, Acute pathology, Leukemia, Myeloid, Acute therapy, Leukocytes pathology, Matrix Metalloproteinase Inhibitors, Oligopeptides pharmacology
- Abstract
Acute myelogenous leukemias (AMLs) are characterized by medullary and extramedullary invasion. We hypothesized that a supramolecular complex, the leukemia-cell invadosome, which contains certain integrins, matrix metalloproteinases (MMPs), and other as-yet unidentified proteins, is essential for tissue invasion and may be central to the phenotypic diversity observed in the clinic. Here we show that the specific binding of MMP-9 to leukocyte surface beta(2) integrin is required for pericellular proteolysis and migration of AML-derived cells. An efficient antileukemia effect was obtained by the hexapeptide HFDDDE, a motif of the MMP-9 catalytic domain that mediates integrin binding: HFDDDE prevented proMMP-9 binding, transmigration through a human endothelial cell layer, and extracellular matrix degradation. Notably, the functional protein anchorage between beta(2) integrin and proMMP-9 described in this study does not involve the enzymatic active sites targeted by known MMP inhibitors. Taken together, our results provide a biochemical working definition for the human leukemia invadosome. Disruption of specific protein complexes within this supramolecular target complex may yield a new class of anti-AML drugs with anti-invasion (rather than or in addition to cytotoxic) attributes. more...
- Published
- 2009
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