Role of leukemia cell invadosome in extramedullary infiltration

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD18 Antigens / genetics
  • CD18 Antigens / metabolism
  • Cell Adhesion
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Enzyme Precursors / antagonists & inhibitors*
  • Enzyme Precursors / genetics
  • Enzyme Precursors / metabolism
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Humans
  • Immunoblotting
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology*
  • Leukemia, Myeloid, Acute / therapy*
  • Leukocytes / pathology*
  • Matrix Metalloproteinase 9 / genetics
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Oligopeptides / pharmacology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Survival Rate
  • Xenograft Model Antitumor Assays

Substances

  • CD18 Antigens
  • Enzyme Precursors
  • Matrix Metalloproteinase Inhibitors
  • Oligopeptides
  • RNA, Messenger
  • pro-matrix metalloproteinase 9
  • Matrix Metalloproteinase 9