Matrix Metalloproteinase-9 Promotes Chronic Lymphocytic Leukemia B Cell Survival through Its Hemopexin Domain

• Published in: Cancer cell 2010-02, Vol.17 (2), p.160-172
• Main Authors: Redondo-Muñoz, Javier, Ugarte-Berzal, Estefanía, Terol, María José, Van den Steen, Philippe E., Hernández del Cerro, Mercedes, Roderfeld, Martin, Roeb, Elke, Opdenakker, Ghislain, García-Marco, José A., García-Pardo, Angeles
• Format: Article
• Language: English
• Subjects: Apoptosis; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; Cell Adhesion; CELLBIO; CELLCYCLE; Cells, Cultured; Gene Expression Regulation, Leukemic; Humans; Integrin alpha4beta1 - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Matrix Metalloproteinase 9 - chemistry; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase 9 - physiology; Mitochondria - metabolism; Mitochondria - ultrastructure; Myeloid Cell Leukemia Sequence 1 Protein; Phosphorylation; Protein Structure, Tertiary; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Signal Transduction; SIGNALING; src-Family Kinases - metabolism; src-Family Kinases - physiology; STAT3 Transcription Factor - metabolism
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2009.12.044

Matrix metalloproteinase-9 (MMP-9) is the major MMP produced by B-CLL cells and contributes to their tissue infiltration by degrading extracellular and membrane-anchored substrates. Here we describe a different function for MMP-9 in B-CLL, which involves the hemopexin domain rather than its catalytic function. Binding of soluble or immobilized (pro)MMP-9, a catalytically inactive proMMP-9 mutant, or the MMP-9 hemopexin domain to its docking receptors α4β1 integrin and CD44v, induces an intracellular signaling pathway that prevents B-CLL apoptosis. This pathway is induced in all B-CLL cases, is active in B-CLL lymphoid tissues, and consists of Lyn activation, STAT3 phosphorylation, and Mcl-1 upregulation. Our results establish that MMP/receptor binding induces intracellular survival signals and highlight the role of (pro)MMP-9 in B-CLL pathogenesis. ► MMP-9/integrin binding induces cell survival signaling by a noncatalytic mechanism ► Lyn, STAT3, and Mcl-1 are key and specific components of the MMP-9 survival pathway ► B-CLL cells in niches have higher surface MMP-9 and viability compared to those in PB ► MMP-9 has an additional function contributing to B-CLL pathogenesis