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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3143-3151.
Prepublished online as a Blood First Edition Paper on July 13, 2006; DOI 10.1182/blood-2006-03-007294.
 Previous Article | Next Article 
Submitted March 3, 2006
Accepted June 21, 2006
MMP-9 in B-cell chronic lymphocytic leukemia is upregulated by  4 1 integrin or CXCR4 engagement via distinct signaling pathways, localizes to podosomes, and is involved in cell invasion and migration
Javier Redondo-Munoz, Elizabeth Escobar-Diaz, Rafael Samaniego, Ma Jose Terol, Jose A Garcia-Marco, and Angeles Garcia-Pardo*
Centro de Investigaciones Biologicas, CSIC, Madrid, Spain
Hospital Gregorio Maranon, Madrid, Spain
Hospital Clinico Universitario, Valencia, Spain
Hospital Universitario Puerta de Hierro, Madrid, Spain
* Corresponding author; email: agarciapardo{at}cib.csic.es.
B-cell chronic lymphocytic leukemia (B-CLL) progression is determined by malignant cell extravasation and lymphoid tissue infiltration. We have studied the role and regulation of matrix metalloproteinase-9 (MMP-9) in B-CLL cell migration and invasion. Adhesion of B-CLL cells to the fibronectin fragment FN-H89, VCAM-1, or TNF- -activated HUVEC, upregulated MMP-9 production, measured by gelatin zymography. This effect was mediated by 4 1 integrin and required PI3-K/Akt signaling. The chemokine CXCL12 also upregulated MMP-9, independently of 41 and involving ERK1/2 but not Akt activity. Accordingly, 41 engagement activated the PI3-K/Akt/NF- B pathway, while CXCL12/CXCR4 interaction activated ERK1/2/c-Fos signaling. Anti-MMP-9 antibodies, the MMP-9 inhibitor TIMP-1, or transfection with three different MMP-9 siRNAs significantly blocked migration through Matrigel or HUVEC. Cell-associated MMP-9 was mainly at the membrane and contained the pro-active and mature forms. Moreover, B-CLL cells formed podosomes upon adhesion to FN-H89, VCAM-1 or fibronectin; MMP-9 localized to podosomes in a PI3-K-dependent manner and degraded a fibronectin/gelatin matrix. Our results are the first to show that MMP-9 is physiologically regulated by 41 integrin and CXCL12 and plays a key role in cell invasion and transendothelial migration, thus contributing to B-CLL progression. MMP-9 could therefore constitute a target for treatment of this malignancy.
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