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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. This Article Full Text (PDF) Supplemental Methods and Figures All Versions of this Article: blood-2006-03-007294v1 108/9/3143    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Redondo-Munoz, J. Articles by Garcia-Pardo, A. Search for Related Content PubMed PubMed Citation Articles by Redondo-Munoz, J. Articles by Garcia-Pardo, A. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 3, 2006 Accepted June 21, 2006 MMP-9 in B-cell chronic lymphocytic leukemia is upregulated by 41 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 41 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

	Copyright © 2006 by American Society of Hematology         Online ISSN: 1528-0020