Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes
C. Ries et al., Matrix metalloproteinase production by bone marrow mononuclear cells from normal individuals and patients with acute and chronic myeloid leukemia or myelodysplastic syndromes, CLIN CANC R, 5(5), 1999, pp. 1115-1124
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.