ABSTRACT
<p><b>BACKGROUND</b>Overwhelming evidences on chronic myeloid leukemia (CML) indicate that patients harbor quiescent CML stem cells that are responsible for blast crisis. While the hematopoietic stem cell (HSC) origin of CML was first suggested over 30 years ago, recently CML-initiating cells beyond HSCs are also being investigated.</p><p><b>METHODS</b>We have previously isolated fetal liver kinase-1-positive (Flk1(+)) cells carrying the BCR/ABL fusion gene from the bone marrow of Ph(+) patients with hemangioblast property. In this study, we isolated CML patient-derived Flk1(+)CD31(-)CD34(-) mesenchymal stem cells (MSCs) and detected their biological characteristics and immunological regulation using fluorescence in situ hybridization (FISH) analysis, fluorescence activated cell sorting (FACS), enzyme-linked immunoadsorbent assay, mixed lymphocyte reaction assays; then we compared these characters with those of the healthy donors.</p><p><b>RESULTS</b>CML patient-derived Flk1(+)CD31(-)CD34(-) MSCs had normal morphology, phenotype and karyotype while appeared impaired in immuno-modulatory function. The capacity of patient Flk1(+)CD31(-)CD34(-) MSCs to inhibit T lymphocyte activation and proliferation was impaired in vitro.</p><p><b>CONCLUSIONS</b>CML patient-derived MSCs have impaired immuno-modulatory functions, suggesting that the dysregulation of hematopoiesis and immune response may originate from MSCs rather than hematopoietic stem cells (HSCs). MSCs might be a potential target for developing efficacious treatment for CML.</p>
Subject(s)
Adolescent , Adult , Female , Humans , Male , Middle Aged , Young Adult , Antigens, CD34 , Genetics , Metabolism , Apoptosis , Blotting, Western , Cell Cycle , Cells, Cultured , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Fusion Proteins, bcr-abl , Genetics , Metabolism , Immunomodulation , In Situ Hybridization, Fluorescence , Karyotype , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Allergy and Immunology , Metabolism , Matrix Metalloproteinase 9 , Genetics , Metabolism , Mesenchymal Stem Cells , Cell Biology , Allergy and Immunology , Platelet Endothelial Cell Adhesion Molecule-1 , Genetics , Metabolism , T-Lymphocytes , Vascular Endothelial Growth Factor Receptor-2 , Genetics , MetabolismABSTRACT
Matrix metalloproteinases (MMPs) have the ability to degrade extracellular matrix components. They abnormally express in a variety of solid tumors and hematologic malignancies, and play an important role in tumor invasion and metastasis through extracellular matrix degradation, which closely relates with the progression and prognosis of the malignant disease. This article reviews progress of study on the mechanism of MMP underlying the pathogenesis of hematologic malignancies, including structure of MMP, regulation mechanism of MMP and its relation with proliferation and differentiation of hematopoietic stem cells (HSC), angiogenesis and tumor immunology and so on.