title: Steroid effects on ZAP-70 and SYK in relation to apoptosis in poor prognosis chronic lymphocytic leukemia.
abstract: There is resurgent interest in glucocorticoids (GCs) in the treatment of poor prognosis chronic lymphocytic leukemia (CLL). Little is known however on how GCs induce apoptosis in CLL. Methylprednisolone (MP) induces apoptosis in ZAP-70 positive CLL more readily than in ZAP-70 negative CLL, which is in contrast to the effects of radiation and chemotherapy. The increased GC sensitivity of ZAP-70+ CLL was studied in relation to the expression status of ZAP-70 and the related signal transducing tyrosine kinase SYK. Both ZAP-70 and SYK were downregulated by GC treatment. Moreover, SYK was dephosphorylated by the phosphatase PTP1B of which the expression and translation levels were induced by GCs. Inhibition of PTP1B successfully restored ZAP-70 expression and SYK phosphorylation but did not interfere with GC-induced apoptosis. Therefore, the downregulation of ZAP-70 and P-SYK per se during treatment with GCs is not sufficient to induce apoptosis, and different mechanisms must therefore be responsible for the increased steroid sensitivity of ZAP-70+ CLL.
authors.affiliation: Department of Hematology, Ghent University Hospital, Ghent, Belgium. Jerina.Boelens@UGent.be
authors.forename: Jerina
authors.initials: J
authors.lastname: Boelens
authors.forename: Sofie
authors.initials: S
authors.lastname: Lust
authors.forename: Femke
authors.initials: F
authors.lastname: Van Bockstaele
authors.forename: Mireille
authors.initials: M
authors.lastname: Van Gele
authors.forename: Ann
authors.initials: A
authors.lastname: Janssens
authors.forename: Lara
authors.initials: L
authors.lastname: Derycke
authors.forename: Barbara
authors.initials: B
authors.lastname: Vanhoecke
authors.forename: Jan
authors.initials: J
authors.lastname: Philippé
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.forename: Fritz
authors.initials: F
authors.lastname: Offner
mesh_terms: D000305:Adrenal Cortex Hormones / Q000627:therapeutic use*; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002699:Chlorambucil / Q000627:therapeutic use; D015536:Down-Regulation; D005434:Flow Cytometry; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008775:Methylprednisolone / Q000627:therapeutic use; D010957:Plasmids; D011379:Prognosis; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072377:Syk Kinase; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D017304:Annexin A5; D047908:Intracellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D002699:Chlorambucil; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; D014740:Vidarabine; C024352:fludarabine; D008775:Methylprednisolone