Role of leukemia cell invadosome in extramedullary infiltration.
Blood
; 114(14): 3008-17, 2009 Oct 01.
Article
en En
| MEDLINE
| ID: mdl-19636064
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.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Oligopéptidos
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Leucemia Mieloide Aguda
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Precursores Enzimáticos
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Inhibidores de la Metaloproteinasa de la Matriz
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Leucocitos
Límite:
Animals
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Humans
Idioma:
En
Año:
2009
Tipo del documento:
Article