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Abstract

B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of mature CD5+ B lymphocytes in the peripheral blood. As the disease progresses, these tumoral cells infiltrate lymphoid tissues. Several molecules that participate in B-CLL cell migration and invasion have been identified. These include the chemokines CCL21, CCL19, and CXCL12, VEGF, and αLβ2 and α4β1 integrins. B-CLL cells produce and secrete gelatinase-B/proMMP-9 and elevated intracellular levels of this MMP correlate with advanced stage and poor patient survival. In this thesis we show that MMP-9 plays an important role in the transendothelial migration, invasion, survival and pathology of B-CLL cells. We have found that secretion of proMMP-9 by B-CLL cells is up-regulated by α4β1 integrin, CXCR4, or CCR7 engagement via different signaling pathways (PI3K/Akt/NF-κB for α4β1 or Erk1, 2/c-fos for CXCR4 and CCR7). Besides up-regulating proMMP-9 levels, α4β1 integrin ligation also induces the formation of podosomes in B-CLL cells and the localization of proteolytically active MMP-9 to these invasive structures. Although mainly present as a secreted soluble form, MMP-9 has also been detected at the B-CLL cell surface. We have studied the molecular associations and possible function of this surface-bound MMP-9. We show that B-CLL cells are able to bind soluble and inmobilized pro- and active MMP-9, in contrast to normal B cells. These interactions are mediated by α4β1 integrin and 190-kDa CD44v, which form a novel docking complex at the B-CLL cell surface. The MMP-9 hemopexin domain is critical for this anchorage. Moreover, surface-bound MMP-9 is functional and regulates B-CLL cell arrest and movement through its catalytic activity. Analyzing other possible roles for surface-bound MMP-9, we describe a novel pathogenic function for this MMP. We show that binding of MMP-9 to B-CLL cells induces an antiapoptotic signaling pathway involving Lyn kinase, STAT3, and myeloid cell leukemia-1 (Mcl-1). Most importantly, induction of this pathway does not require MMP-9 proteolytic activity, but is rather due to the interaction of MMP-9 with its surface receptors. Thus, MMP-9 possesses previously unknown properties contributing to survival and progression of B-CLL.