Steroid effects on ZAP-70 and SYK in relation to apoptosis in poor prognosis chronic lymphocytic leukemia.
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.
Boelens
Jerina
J
Department of Hematology, Ghent University Hospital, Ghent, Belgium. Jerina.Boelens@UGent.be
Lust
Sofie
S
Van Bockstaele
Femke
F
Van Gele
Mireille
M
Janssens
Ann
A
Derycke
Lara
L
Vanhoecke
Barbara
B
Philippé
Jan
J
Bracke
Marc
M
Offner
Fritz
F
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
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