Blood Journal
Leading the way in experimental and clinical research in hematology

Role of leukemia cell invadosome in extramedullary infiltration

  1. Michael Stefanidakis1,2,*,
  2. Katja Karjalainen1,2,*,
  3. Diana E. Jaalouk2,
  4. Carl G. Gahmberg1,
  5. Susan O'Brien2,
  6. Renata Pasqualini2,
  7. Wadih Arap2, and
  8. Erkki Koivunen1,2
  1. 1Department of Biological and Environmental Sciences, Division of Biochemistry, University of Helsinki, Helsinki, Finland; and
  2. 2The University of Texas M. D. Anderson Cancer Center, Houston

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 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.

  • Submitted April 8, 2008.
  • Accepted July 12, 2009.
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