Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes

The two matrix metalloproteinases (MMPs) M-r 72,000 type IV collagenase (MM P-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 ext racellular matrix barriers. We have investigated the production of these tw o enzymes as well as the membrane-type MMP (MT1-MMP) and the tissue inhibit ors of metalloproteinases (TIMPs) TIMP-1 and TIMP-2 in the bone marrow mono nuclear cells (BM-MNCs) of patients with acute myeloid leukemia (AML; n = 2 4), chronic myeloid leukemia (CML; n = 17), myelodysplastic syndromes (MDS; n = 8), and healthy donors (n = 5), Zymographic analysis of BM-MNC conditi oned medium showed that a M-r 92,000 gelatinolytic activity, identified as MMP-8 by Western blotting, was constitutively released from cells of all pa tients and healthy individuals examined in this study. In contrast, MMP-2 s ecretion was found to be absent in all samples from healthy donors but pres ent 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 case s, both patients either being in or preceding blast crisis. In MDS, MMP-2 w as found in three of eight (38%) of the patients, two of them undergoing pr ogression 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 h ealthy donors and CML samples, than in AML and MDS, Reverse transcriptase-P CR analysis revealed the presence of TIMP-2 mRNA in the majority of MMP-2-r eleasing BM-MNCs. MT1-MMP expression was present in most samples of patient s 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 demonstra ted that leukemic blast cells additionally secrete MMP-2 representing a pot ential marker for dissemination in myeloproliferative malignancies.