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 Blood, 1 October 2009, Vol. 114, No. 14, pp. 3008-3017.
Prepublished online as a Blood First Edition Paper on July 27, 2009; DOI 10.1182/blood-2008-04-148643.

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MYELOID NEOPLASIA

Role of leukemia cell invadosome in extramedullary infiltration

Michael Stefanidakis1,2,*, Katja Karjalainen1,2,*, Diana E. Jaalouk2, Carl G. Gahmberg1, Susan O'Brien2, Renata Pasqualini2, Wadih Arap2, and Erkki Koivunen1,2

1 Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Helsinki, Finland; and 2 The University of Texas M. D. Anderson Cancer Center, Houston

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 β2 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 β2 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.


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