期刊
BLOOD
卷 114, 期 14, 页码 3008-3017出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-04-148643
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资金
- Academy of Finland
- Finnish Cancer Society
- Magnus Ehrnrooth Foundation
- Helsingin Sanomat Foundation
- Developmental SPORE
- Specialized Program in Research Excellence (SPORE) in Leukemia
- National Institutes of Health/National Cancer Institute [P50CA100632]
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. (Blood. 2009; 114: 3008-3017)
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