Abstract
Abstract Chronic lymphocytic leukemia (CLL) cells secrete matrix metalloproteinase-9 (MMP-9) and express it on their surface. We previously showed that surface-bound MMP-9 binds to alpha4beta1 integrin and CD44v and contributes to CLL progression since: 1) elicits a signalling pathway that leads to cell survival, and 2) regulates in vitro cell migration (Redondo-Muñoz et al., Blood, 2008; Cancer Cell, 2010). We have now addressed the effect of MMP-9 overexpression. a situation likely occurring at CLL niches, in CLL cell migration. We have used primary CLL cells and CLL-derived MEC-1 cells transfected with empty (Mock-cells) or proMMP-9-encoding (MMP-9-cells) lentiviral vectors. The constitutive (pro)MMP-9 expression in Mock-cells and primary CLL cells was similar, whereas in MMP-9-cells expression resembled that of CLL cells incubated with proMMP-9. In vivo experiments using NOD/SCID mice showed that MMP-9-cells had significantly impaired homing to bone marrow and spleen, compared to Mock-cells. Importantly, incubation of primary CLL cells with proMMP-9 inhibited their homing to these organs. This inhibition was specific, dose-dependent, and observed in all CLL samples tested, independently of prognostic markers or disease stage. Additionally, the MMP-9 catalytic activity was only partially involved, as the inactive mutant proMMP-9MutE had a partial effect. MMP-9-cells also showed impaired migration in vitro, which was reverted by reducing (pro)MMP-9 expression with siRNAs. Biochemical analysis of the (pro)MMP-9 effect indicated that MMP-9-cells or primary CLL cells incubated with proMMP-9 had reduced activation of migration regulatory molecules, including RhoAGTPase, Akt, ERK, and FAK. In contrast, p190RhoGAP (RhoA inhibitor) and PTEN (Akt/ERK/FAK inhibitor) were upregulated in MMP-9-cells. Reduction of (pro)MMP-9 expression by siRNAs restored RhoA activity and diminished PTEN levels. Moreover, gene expression analyses on Mock and MMP-9 cells using microarrays revealed 129 genes differentially expressed in MMP-9 cells compared to Mock cells. The identified genes were involved in cell adhesion and migration as well as leukocyte activation. Our results reveal novel functions for (pro)MMP-9 in modulating signaling pathways and gene expression in CLL. Therefore, elevated local expression of (pro)MMP-9 may contribute to malignant cell retention in lymphoid organs and disease progression. Supported by grants SAF2012-31613 and RD12/0036/0061 (AGP) from the Ministry of Economy and Innovation, Spain; S2010/BMD-2314 (AGP) from the Comunidad de Madrid/European Union, and by a grant from the Fundación Puerta de Hierro, Madrid (JAGM). Citation Format: Elvira Bailón, Estefanía Ugarte-Berzal, Irene Amigo-Jiménez, José A. García-Marco, Angeles García-Pardo. Novel functions of matrix metalloproteinase-9 contributing to B-cell chronic lymphocytic leukemia progression. [abstract]. In: Proceedings of the AACR Special Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(17 Suppl):Abstract nr A03.
Published Version
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