Maria Honnemyr1, Øystein Bruserud2,3, Annette K Brenner1,4. 1. Section for Hematology, Department of Clinical Science, Haukeland University Hospital, University of Bergen, 5021, Bergen, Norway. 2. Section for Hematology, Department of Clinical Science, Haukeland University Hospital, University of Bergen, 5021, Bergen, Norway. oystein.bruserud@helse-bergen.no. 3. Department of Medicine, Haukeland University Hospital, Bergen, Norway. oystein.bruserud@helse-bergen.no. 4. Department of Medicine, Haukeland University Hospital, Bergen, Norway.
Abstract
INTRODUCTION: Acute myeloid leukemia (AML) cells show constitutive release of matrix metalloproteases and their inhibitors. We now investigated this constitutive release of protease/protease regulators associated with carcinogenesis (ADAM12, uPA, cystatin B), angiogenesis (serpin E1, uPA, CD147), cancer cell migration (uPA, cystatin C), coagulation (ADAM TS13, serpin C1), inflammation (fetuin A, caspase 1, cystatin C), monocytic differentiation (CFD) or regulation of hematopoiesis (neutrophil elastase). METHODS: AML blasts from 79 consecutive patients were cultured in serum-free medium and mediator levels determined in culture supernatants. RESULTS: Detectable release of serpin C1 and E1, cystatin B and C, CD147 and uPA was seen for most patients. These mediators together with fetuin A, caspase 1, and CFD were included in a hierarchical clustering analysis and three patient subsets were identified (high, intermediate, and low release). High levels were associated with monocytic differentiation. Global gene expression analyses showed increased levels of several zinc finger proteins for low-release patients and high expression of several cell surface molecules, ATPases, and calcium-binding proteins for high-release patients. Constitutive release of several mediators was also seen for normal hematopoietic cells and mesenchymal stem cells. In cocultures of the latter and AML blasts, the release level for most mediators was altered to resemble the levels of the mesenchymal cells cultured alone. CONCLUSION: Differences in constitutive release of protease/protease regulators are a part of the disease heterogeneity in AML.
INTRODUCTION:Acute myeloid leukemia (AML) cells show constitutive release of matrix metalloproteases and their inhibitors. We now investigated this constitutive release of protease/protease regulators associated with carcinogenesis (ADAM12, uPA, cystatin B), angiogenesis (serpin E1, uPA, CD147), cancer cell migration (uPA, cystatin C), coagulation (ADAM TS13, serpin C1), inflammation (fetuin A, caspase 1, cystatin C), monocytic differentiation (CFD) or regulation of hematopoiesis (neutrophil elastase). METHODS:AML blasts from 79 consecutive patients were cultured in serum-free medium and mediator levels determined in culture supernatants. RESULTS: Detectable release of serpin C1 and E1, cystatin B and C, CD147 and uPA was seen for most patients. These mediators together with fetuin A, caspase 1, and CFD were included in a hierarchical clustering analysis and three patient subsets were identified (high, intermediate, and low release). High levels were associated with monocytic differentiation. Global gene expression analyses showed increased levels of several zinc finger proteins for low-release patients and high expression of several cell surface molecules, ATPases, and calcium-binding proteins for high-release patients. Constitutive release of several mediators was also seen for normal hematopoietic cells and mesenchymal stem cells. In cocultures of the latter and AML blasts, the release level for most mediators was altered to resemble the levels of the mesenchymal cells cultured alone. CONCLUSION: Differences in constitutive release of protease/protease regulators are a part of the disease heterogeneity in AML.
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