Gang of 3 in aggressive CLL?

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.

The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous. Although a substantial and growing number of biological prognostic factors have been identified, the enlargement of lymphoid organs and the replacement of bone marrow elements by a leukemic clone remain the hallmarks of progression in CLL. These features are the cornerstones in the Rai and Binet staging systems and the primary determining factors in deciding when to initiate therapy.¹  Thus, understanding the factors that regulate tissue invasion by CLL B cells is a critical aspect of CLL biology that is also essential for effective therapeutic targeting of the tumor-microenvironment interface.

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.