Constitutive activation of the MAPkinase p38 is critical for MMP-9 production and survival of B-CLL cells on bone marrow stromal cells.
In the present work we investigated the role and biological significance of mitogen activated protein kinases (MAPK) in B-cell chronic lymphocytic leukaemia (B-CLL). The MAPK p38 was constitutively activated in B-CLL, but not in normal peripheral B cells. In addition, we demonstrated that the upstream kinases of p38, MKK3/6 were also constitutively activated in B-CLL cells. Furthermore, we determined by EMSA that the p38 MAP kinase pathway was not linked to the constitutive high expression of NF-kappaB, a critical survival factor of B-CLL cells. Recently, it has been shown that serum levels of angiogenic factors like VEGF, bFGF and MMP-9 are elevated in the serum of CLL patients and correlate with an unfavorable prognosis. We showed that the constitutive expression of MMP-9 was dependent on p38-activity and inhibition of p38 strongly downregulated MMP-9 expression. Coculture of B-CLL cells and stromal cells can protect spontaneous apoptosis of leukemic B cells. To determine the role of permanently activated p38 and MMP-9 expression, we cocultured B-CLL cells with bone marrow stromal cells. Survival of B-CLL cells on stroma was severely impaired when p38 was inhibited. Furthermore, blockade of MMP-9 activity also antagonized the antiapoptotic effect of stromal cells.
Ringshausen
I
I
IIIrd Department of Medicine, Technical University of Munich, Munich, Germany. iringshausen@cc.ucsf.edu
Dechow
T
T
Schneller
F
F
Weick
K
K
Oelsner
M
M
Peschel
C
C
Decker
T
T
D017209:Apoptosis; D001854:Bone Marrow Cells / Q000201:enzymology*; D018920:Coculture Techniques; D024202:Electrophoretic Mobility Shift Assay; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000473:pathology; D048371:MAP Kinase Kinase 3 / Q000378:metabolism; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D017154:Stromal Cells / Q000201:enzymology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D048051:p38 Mitogen-Activated Protein Kinases; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human; D020780:Matrix Metalloproteinase 9