Plasminogen activation in human acute leukaemias

Scherrer, Anne Paule Marie; Wohlwend, Annelise Isabelle; Kruithof, EK; Vassalli, J.-D.; Sappino, André‐Pascal

doi:10.1046/j.1365-2141.1999.01432.x

Cited by 22 publications

(19 citation statements)

References 50 publications

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“…36,37 In leukemias, it has been shown that PAI-2 is up-regulated in M2 and M4 to M5 types and is thought to be responsible for the invasive phenotype of these cells. 23 Consistent with these observations we have also shown that hematopoietic cells forced to express ZNF198/FGFR1 also up-regulate PAI-2. In a report, PAI-2 was also shown to bind to the retinoblastoma (RB1) protein and protect it from degradation by an as yet unknown protease.…”

Section: Discussionsupporting

confidence: 77%

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Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease

Kasyapa

Kunapuli

Hawthorn

et al. 2006

Blood

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The ZNF198/FGFR1 fusion kinase associated with an atypical myeloproliferative disease is constitutively activated and regulates several STAT transcription factors. We used oligonucleotide microarrays to compare the gene-expression profiles between HEK-293 cells that stably express either the ZNF198/FGFR1 chimeric protein or the wild-type ZNF198 gene. Expression of the plasminogen activator inhibitor-2 (PAI-2/SERPINB2) was highly increased in cells expressing the fusion gene. Western blot analysis demonstrated that HEK-293 cells do not express PAI-2 endogenously, but in ZNF198/ FGFR1-expressing cells 2 molecular forms of PAI-2, which were 47 kDa and 32 kDa, were expressed intracellularly, and a 60-kDa form was secreted. Similarly, expression of ZNF198/FGFR1 in BaF/3 mouse hematopoietic cells also induced the expression of the PAI-2 protein. Immu IntroductionReciprocal chromosomal translocations in hematologic malignancies often result in the generation of novel fusion proteins. These chimeric proteins generally provide novel signaling functions that are considered to account for the oncogenic events in the leukemic cells. 1 One such chromosomal translocation was described in patients with an atypical form of myeloproliferative disease (MPD) that is associated with T-cell leukemia/lymphoma and peripheralblood eosinophilia 2 and involves a reciprocal t(8;13)(p11;q12) rearrangement. [3][4][5][6][7][8] In this translocation a zinc finger gene, ZNF198, is fused in-frame with the fibroblast growth factor receptor 1 (FGFR1). The resultant protein contains the zinc finger motif and proline-rich domain of ZNF198 and the intracellular tyrosine kinase domain of FGFR1. [9][10][11][12] The resulting ZNF198/FGFR1 fusion protein is a ligand-independent, constitutively active cytoplasmic tyrosine kinase, unlike FGFR1, which is a membrane-bound receptor tyrosine kinase. Although the signaling functions of the ZNF198/FGFR1 fusion kinase were proposed based on the functions of FGFR1, the fusion kinase has been suggested to have unique signaling functions that are different from FGFR1 because of its cytoplasmic localization and constitutive tyrosine kinase activity. [13][14] The oncogenic potential of the ZNF198/FGFR1 fusion kinase was demonstrated in IL-3-dependent Ba/F3 cells, where stable expression of the chimeric fusion protein produced IL-3-independent growth. [15][16][17] Although activation of FGFR1 is known to result from dimerization following ligand binding, the ZNF198/ FGFR1 fusion kinase is activated through homodimerization of the ZNF198 zinc finger domain. [14][15][16] ZNF198 is a widely expressed gene that encodes a 1377-amino acid nuclear protein with a molecular mass of 155 kDa. [9][10][11][12] Prominent features of ZNF198 are the 5 zinc finger motifs and a proline-rich domain (PRD) within the central part of the protein and an acidic domain at the C-terminal end of the protein. 9 On the basis of the structure and the type of zinc fingers present in ZNF198, it has been predicted to have a function in protein-prote...

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Section: Discussionsupporting

confidence: 77%

“…23 This finding prompted us to focus further on the role of PAI-2 up-regulation in ZNF198/FGFR1 fusion kinase-expressing cells. RT-PCR and Western blot analyses were used to analyze HEK-293 cells which expressed GFP, ZNF198, or ZNF198/FGFR1.…”

Section: Analysis Of Pai-2 Expression In Znf198/fgfr1-expressing Cellsmentioning

confidence: 99%

Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease

Kasyapa

Kunapuli

Hawthorn

et al. 2006

Blood

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“…Previous reports suggest that the secretion of PAs by myeloid cells is linked to their differentiation, tPA is being produced by normal myeloid progenitor cells whereas, uPA is produced by more mature myeloid cells (Vassalli et al. , 1991; Scherrer et al. , 1999).…”

Section: Discussionmentioning

confidence: 99%

The relation between plasminogen activator inhibitor activity and disease activation in acute myeloblastic leukaemia patients

et al. 2006

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Coagulation and fibrinolytic abnormalities are common in patients with acute myeloblastic leukaemia (AML) like other forms of leukaemias. In this study, we investigated if total plasminogen activator inhibitor (PAI) activity, which is believed to increase in initial diagnosis and relapse in AML patients could be accepted as a relapse criterion or not. Total of 34 AML patients and 18 healthy volunteers were included in this study. The patients' diagnosis were based on clinical criteria as well as morphological, cytochemical, immunuphenotypic examinations of peripheral blood and bone marrow specimens. Total PAI activity was measured with Dade Behring Bericrom PAI reagent in BCS system. Total PAI activity was higher than 3.5 U/ml in 11 AML patients while it was normal (0.3-3.5 U/ml) in control group (P < 0.01). There was no significant difference in total PAI activity between AML subgroups (P > 0.05). We found significant difference in total PAI activity between patients who have active disease and remission. In conclusion, the total PAI activity could be accepted as a relapse and an initial diagnosis criterion of AML patients during follow up.

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“…In the same study, uPAR mRNAwas also present in two cases of T-cell type ALL but not in any early B-type ALL cases. 112 Multiple myeloma is a B-cell malignancy, and the expression uPAR in myeloma cells varies in different reports. In myeloma cell lines and in patients with multiple myeloma, uPAR was found to be expressed using flow cytometry.…”

Section: K Leukemiamentioning

confidence: 99%

Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer

Bock

Wang

2003

Medicinal Research Reviews

136

103

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The involvement of the urokinase-type plasminogen activator (uPA) system in particular has been extensively studied in the pathogenesis of cancer. The molecular role of the uPA receptor (uPAR) is well characterized with its participation in cell migration and extracellular matrix (ECM) degradation. Over-expression of uPAR in cancer has been demonstrated in many studies and is considered an attractive target for anticancer agents. We and others have down-regulated uPAR expression in an attempt to inhibit cancer metastasis based on its molecular role. Uniquely, uPAR which is a glycosyl phosphatidylinositol anchored protein is not only bound to the cell surface but also has a soluble form, suPAR. There is now accumulated clinical and experimental evidence supporting the significant role of uPAR and its soluble counterpart in a number of solid cancers. The expression of uPAR can be associated with tumor cells or stromal cells or both. Differences observed in the expression of uPAR using immunohistochemistry (IHC) are likely explained by the use of different antibodies and techniques rather than true cellular differences and are reviewed here. This review summarizes the clinical relevance of uPAR and its soluble form in the prognosis and diagnosis of different cancers.

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Plasminogen activation in human acute leukaemias

Cited by 22 publications

References 50 publications

Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease

Induction of the plasminogen activator inhibitor-2 in cells expressing the ZNF198/FGFR1 fusion kinase that is involved in atypical myeloproliferative disease

The relation between plasminogen activator inhibitor activity and disease activation in acute myeloblastic leukaemia patients

Clinical significance of urokinase‐type plasminogen activator receptor (uPAR) expression in cancer

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