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Blood, 1 July 2008, Vol. 112, No. 1, pp. 5-6.
Gang of 3 in aggressive CLL?MAYO CLINIC
In this issue of Blood, Redondo-Muñoz and colleagues demonstrate that VLA-4 and the 190-kDa isoform of CD44v constitute docking molecules on the surface of CLL B cells for MMP-9. The attachment of MMP-9 to the surface of CLL B cells appears to alter their migration.
VLA-4, CD44, and MMP-9 all play important roles in the interaction between CLL B cells and microenvironment. High expression of VLA-4 and CD44 by CLL B cells and a high level of secreted MMP-9 are associated with a poor outcome.2–4 New work by Redondo-Munoz and colleagues uncovers a link between the 3 molecules. The authors convincingly show that VLA-4 and the 190-kDa isoform of CD44v form a docking complex on the surface of CLL B cells for MMP-9 secreted by leukemic cells. It also appears that activation of pro–MMP-9 is triggered by its binding to the VLA-4/CD44v complex. How the binding of MMP-9 to the cell surface affects the invasiveness and migration of leukemic cells is less clear. Although it has been previously shown that MMP-9 facilitates the migration of CLL B cells, in this study the authors indirectly demonstrate that binding of MMP-9 to the cell surface may actually arrest migration. Migration arrest, in turn, may lead to an accumulation of leukemic cells in affected organs. Thus, the strong association of high VLA-4 and CD44 expression with aggressive disease may, in part, be related to interaction with MMP-9—a hypothesis with intriguing potential therapeutic implications. The anti–VLA-4 antibody natalizumab (Biogen IDEC), approved for the treatment of multiple sclerosis,5 is now being tested in clinical studies of hematological malignancies (multiple myeloma). Although the primary rationale for anti–VLA-4 therapy is to interrupt VLA-4 binding to VCAM-1 and fibronectin to prevent resulting homing and signaling, it will be important to investigate the impact of anti–VLA-4 therapy on localization of MMP-9 on the cell surface and cell migration. Similarly, anti-CD44 antibodies, also under development for the treatment of human cancer, may have an impact on the surface binding of MMP-9. An interesting technical achievement by Redondo-Muñoz and colleagues is the very high efficiency of siRNA transfection of primary CLL B cells with little induction of apoptosis. Transfection of primary CLL B cells is technically challenging and typically observed low transfection frequencies have been a major obstacle in CLL research. The transfection strategy used by the authors, if reproducible by other researchers, may be a significant step forward.
Footnotes
Conflict-of-interest disclosure: The author declares no competing financial interests.
REFERENCES
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| Copyright © 2008 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||||
4β1 integrin and 190-kDa CD44v constitute a cell surface docking complex for gelatinase B/MMP-9 in chronic leukemic but not in normal B cells
