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Blood. 2009 Oct 1;114(14):3008-17. doi: 10.1182/blood-2008-04-148643. Epub 2009 Jul 27.

Role of leukemia cell invadosome in extramedullary infiltration.

Author information

1
Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Helsinki, Finland.

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.

PMID:
19636064
PMCID:
PMC2756207
DOI:
10.1182/blood-2008-04-148643
[Indexed for MEDLINE]
Free PMC Article

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