2026-06-29T07:36:35Zhttps://docta.ucm.es/rest/oai/request

oai:docta.ucm.es:20.500.14352/475192023-09-14T10:59:38Zcom_20.500.14352_14col_20.500.14352_22

Regulación y función de la metaloproteinasa de matriz (MMP-9) en la leucemia linfocítica crónica-B y su papel en la patogénesis de la enfermedad Redondo Muñoz, Javier García Pardo, María de los Ángeles 616.155.392.2-036.12(043.2) Metaloproteinasa de matriz Leucemia Leucemia linfocítica Leukemia Lymphocytic leukemia Biología celular (Biología) 2407 Biología Celular 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. Depto. de Biología Celular Fac. de Ciencias Biológicas TRUE pub 2023-06-20T06:35:42Z 2023-06-20T06:35:42Z 2010-11-22 2010-03-25 doctoral thesis https://hdl.handle.net/20.500.14352/47519 XXXX-XXXX spa open access application/pdf Universidad Complutense de Madrid, Servicio de Publicaciones