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Blood, 1 July 2008, Vol. 112, No. 1, pp. 169-178.
Prepublished online as a Blood First Edition Paper on March 7, 2008; DOI 10.1182/blood-2007-08-109249.


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Submitted August 24, 2007
Accepted March 5, 2008

{alpha}4{beta}1 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

Javier Redondo-Munoz, Estefania Ugarte-Berzal, Jose A Garcia-Marco, Mercedes Hernandez del Cerro, Philippe E. Van den Steen, Ghislain Opdenakker, Maria Jose Terol, and Angeles Garcia-Pardo*

Departamento de Fisiopatologia Celular y Molecular, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain
Servicio de Hematologia, Hospital Puerta de Hierro, Madrid, Spain
Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
Servicio de Hematologia y Medicina Oncologica, Hospital Clinico, Valencia, Spain

* Corresponding author; email: agarciapardo{at}cib.csic.es.

As B-cell chronic lymphocytic leukemia (B-CLL) progresses, malignant cells extravasate and infiltrate lymphoid tissues. Several molecules, including gelatinase B/MMP-9, contribute to these processes. Although mainly a secreted protease, some MMP-9 is present at the B-CLL cell surface and the function, mode of anchoring and interactions of this MMP-9 are unknown. Here we show that anti-MMP-9 antibodies immunoprecipitated a 190 kDa CD44v isoform and {alpha}4{beta}1 integrin from B-CLL cells, but not from normal B cells. Function-blocking antibodies to {alpha}4{beta}1 or CD44 or transfection with specific siRNAs, decreased cell-associated proMMP-9 and increased the secreted form. B-CLL cells attached to and bound pro- and active MMP-9 and this was inhibited by blocking the expression or function of {alpha}4{beta}1 or CD44. The MMP-9 hemopexin domain was critical in these interactions. {alpha}4{beta}1 and 190 kDa CD44v (but not CD44H) formed a complex at the cell surface, since they both co-immunoprecipitated with anti-{alpha}4, anti-{beta}1 or anti-CD44 antibodies. Immunofluorescence analyses confirmed that {alpha}4{beta}1 and CD44v colocalized with MMP-9. Binding of proMMP-9 inhibited B-CLL cell migration and this required MMP-9 proteolytic activity. Thus, we have identified {alpha}4{beta}1 and CD44v as a novel proMMP-9 cell surface docking complex and we show that cell-associated MMP-9 may regulate B-CLL cell migration and arrest.


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