Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain

Javier Redondo-Muñoz; Estefanía Ugarte-Berzal; María José Terol; Philippe E Van den Steen; Mercedes Hernández del Cerro; Martin Roderfeld; Elke Roeb; Ghislain Opdenakker; José A García-Marco; Angeles García-Pardo

doi:10.1016/j.ccr.2009.12.044

Matrix metalloproteinase-9 promotes chronic lymphocytic leukemia b cell survival through its hemopexin domain

Cancer Cell. 2010 Feb 17;17(2):160-72. doi: 10.1016/j.ccr.2009.12.044.

Authors

Javier Redondo-Muñoz¹, Estefanía Ugarte-Berzal, María José Terol, Philippe E Van den Steen, Mercedes Hernández del Cerro, Martin Roderfeld, Elke Roeb, Ghislain Opdenakker, José A García-Marco, Angeles García-Pardo

Affiliation

¹ Centro de Investigaciones Biológicas, Madrid, Spain.

PMID: 20159608
DOI: 10.1016/j.ccr.2009.12.044

Abstract

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 alpha4beta1 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis
B-Lymphocytes / metabolism
B-Lymphocytes / pathology
Cell Adhesion
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
STAT3 Transcription Factor / metabolism
Signal Transduction
src-Family Kinases / metabolism
src-Family Kinases / physiology

Substances

Integrin alpha4beta1
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2
STAT3 Transcription Factor
STAT3 protein, human
lyn protein-tyrosine kinase
src-Family Kinases
Matrix Metalloproteinase 9