Matrix Metalloproteinase Production by Bone Marrow Mononuclear Cells from Normal Individuals and Patients with Acute and Chronic Myeloid Leukemia or Myelodysplastic Syndromes

• Published in: Clinical cancer research Vol. 5; no. 5; pp. 1115 - 1124
• Main Authors: RIES, C, LOHER, F, ZANG, C, ISMAIR, M. G, PETRIDES, P. E
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.1999
• Subjects: Acute Disease; Adult; Aged; Biological and medical sciences; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - genetics; Blast Crisis - enzymology; Blast Crisis - pathology; Blotting, Northern; Blotting, Western; Bone Marrow Cells - enzymology; Cells, Cultured; Collagenases - biosynthesis; Collagenases - genetics; Culture Media, Conditioned; Enzyme Induction; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Leukemic; Hematologic and hematopoietic diseases; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Leukemia, Myeloid - enzymology; Leukemia, Myeloid - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinases, Membrane-Associated; Medical sciences; Metalloendopeptidases - biosynthesis; Metalloendopeptidases - genetics; Middle Aged; Monocytes - enzymology; Myelodysplastic Syndromes - enzymology; Myelodysplastic Syndromes - genetics; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasms, Second Primary - enzymology; Neoplasms, Second Primary - pathology; Neoplastic Stem Cells - enzymology; Neoplastic Stem Cells - pathology; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - biosynthesis; RNA, Neoplasm - biosynthesis; Tissue Inhibitor of Metalloproteinase-1 - biosynthesis; Tissue Inhibitor of Metalloproteinase-1 - genetics; Tissue Inhibitor of Metalloproteinase-2 - biosynthesis; Tissue Inhibitor of Metalloproteinase-2 - genetics; Tumor Cells, Cultured; Human; Enzyme; Gene product; Acute; Metalloendopeptidases; Malignant hemopathy; Tumoral marker; Gene expression; Myelodysplastic syndrome; Myeloproliferative syndrome; Peptidases; Chronic; Mononuclear cell; Enzymatic activity; Chronic myelocytic leukemia; Bone marrow; Hydrolases; Acute myelocytic leukemia
• ISSN: 1078-0432; 1557-3265

The two matrix metalloproteinases (MMPs) M r 72,000 type IV collagenase (MMP-2, gelatinase A) and M r 92,000 type IV collagenase (MMP-9, gelatinase B) play key roles in tissue remodeling and tumor invasion by digestion of extracellular matrix barriers. We have investigated the production of these two enzymes as well as the membrane-type MMP (MT1-MMP) and the tissue inhibitors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 in the bone marrow mononuclear cells (BM-MNCs) of patients with acute myeloid leukemia (AML; n = 24), chronic myeloid leukemia (CML; n = 17), myelodysplastic syndromes (MDS; n = 8), and healthy donors ( n = 5). Zymographic analysis of BM-MNC-conditioned medium showed that a M r 92,000 gelatinolytic activity, identified as MMP-9 by Western blotting, was constitutively released from cells of all patients and healthy individuals examined in this study. In contrast, MMP-2 secretion was found to be absent in all samples from healthy donors but present in 8 of 11 (73%) of the samples from patients with primary AML, 7 of 8 (88%) with secondary AML, and only 1 of 5 (20%) cases with AML in remission, indicating MMP-2 to be produced by the leukemic blasts. MMP-2 release was not detected in CML cell-conditioned medium with the exception of two cases, both patients either being in or preceding blast crisis. In MDS, MMP-2 was found in three of eight (38%) of the patients, two of them undergoing progression of disease within 12 months. Quantitative Northern blot analysis in freshly isolated BM-MNCs showed a relatively low constitutive expression of TIMP-1 in all samples, whereas MMP-9 gene transcription was higher in healthy donors and CML samples, than in AML and MDS. Reverse transcriptase-PCR analysis revealed the presence of TIMP-2 mRNA in the majority of MMP-2-releasing BM-MNCs. MT1-MMP expression was present in most samples of patients with MDS or AML but absent in those with secondary AML and CML. Thus, we have shown that BM-MNCs continuously produce MMP-9 and TIMP-1 and demonstrated that leukemic blast cells additionally secrete MMP-2 representing a potential marker for dissemination in myeloproliferative malignancies.