title: Leukomogenic factors downregulate heparanase expression in acute myeloid leukemia cells.
abstract: Heparanase is a heparan sulfate-degrading endoglycosidase expressed by mature monocytes and myeloid cells, but not by immature hematopoietic progenitors. Heparanase gene expression is upregulated during differentiation of immature myeloid cells. PML-RARalpha and PLZF-RARalpha fusion gene products associated with acute promyelocytic leukemia abrogate myeloid differentiation and heparanase expression. AML-Eto, a translocation product associated with AML FAB M2, also downregulates heparanase gene expression. The common mechanism that underlines the activity of these three fusion gene products involves the recruitment of histone deacetylase complexes to specific locations within the DNA. We found that retinoic acid that dissociates PML-RARalpha from the DNA, and which is used to treat acute promyelocytic leukemia patients, restores heparanase expression to normal levels in an acute promyelocytic leukemia cell line. The retinoic acid effects were also observed in primary acute promyelocytic leukemia cells and in a retinoic acid-treated acute promyelocytic leukemia patient. Histone deacetylase inhibitor reverses the downregulation of heparanase expression induced by the AML-Eto fusion gene product in M2 type AML. In summary, we have characterized a link between leukomogenic factors and the downregulation of heparanase in myeloid leukemic cells.
authors.affiliation: The Hematology Institute, Sourasky Medical Center, Tel-Aviv, Israel.
authors.forename: Rinat
authors.initials: R
authors.lastname: Eshel
authors.forename: Olga
authors.initials: O
authors.lastname: Ben-Zaken
authors.forename: Oded
authors.initials: O
authors.lastname: Vainas
authors.forename: Yona
authors.initials: Y
authors.lastname: Nadir
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Aaron
authors.initials: A
authors.lastname: Polliack
authors.forename: Ella
authors.initials: E
authors.lastname: Naparstek
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Katz
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D000099175:Heparanase