Role of leukemia cell invadosome in extramedullary infiltration.
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.
Stefanidakis
Michael
M
Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Helsinki, Finland.
Karjalainen
Katja
K
Jaalouk
Diana E
DE
Gahmberg
Carl G
CG
O'Brien
Susan
S
Pasqualini
Renata
R
Arap
Wadih
W
Koivunen
Erkki
E
D000818:Animals; D018821:CD18 Antigens / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D004792:Enzyme Precursors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism / Q000473:pathology* / Q000628:therapy*; D007962:Leukocytes / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009842:Oligopeptides / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D018821:CD18 Antigens; D004792:Enzyme Precursors; D061965:Matrix Metalloproteinase Inhibitors; D009842:Oligopeptides; D012333:RNA, Messenger; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9