title: Correlation between ZAP-70, phospho-ZAP-70, and phospho-Syk expression in leukemic cells from patients with CLL.
abstract: For patients with chronic lymphocytic leukemia (CLL), expression of ZAP-70 in the leukemic cells is an indicator of poor prognosis. However, the mechanism that accounts for this effect is not known. ZAP-70 expression has previously been associated with increased B cell antigen receptor signaling upon surface immunoglobulin ligation in vitro as shown by ZAP-70 and Syk phosphorylation. This finding has led to the suggestion that a more aggressive clinical course is correlated with B cell antigen receptor signaling. Using high resolution immunophenotyping to analyze CLL cells ex vivo (without stimulation in vitro), we have demonstrated CLL cells from all patients express some ZAP-70 and that increased expression of ZAP-70 is correlated with decreased levels of phosphorylated ZAP-70 and phosphorylated Syk measured directly ex vivo. Conversely, high levels of phosphorylated ZAP-70 and phosphorylated Syk are found only in samples with low levels of ZAP-70 expression, and Syk and ZAP-70 phosphorylation appear to be mostly independent of each other. Additionally, Syk phosphorylation is directly correlated with levels of p21(cip1), a cell cycle inhibitor and a p53 target. Together these findings suggest that lower levels of p21(cip1) and/or a defect in p53 activity may account in part for the more aggressive disease course in patients with high levels of ZAP-70 rather than enhanced B cell antigen receptor signaling as has been previously hypothesized.
authors.affiliation: Department of Pathology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio 44106, USA. david.kaplan@case.edu
authors.forename: David
authors.initials: D
authors.lastname: Kaplan
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Meyerson
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Li
authors.forename: Carly
authors.initials: C
authors.lastname: Drasny
authors.forename: Fangfang
authors.initials: F
authors.lastname: Liu
authors.forename: Mark
authors.initials: M
authors.lastname: Costaldi
authors.forename: Paul
authors.initials: P
authors.lastname: Barr
authors.forename: Hillard M
authors.initials: HM
authors.lastname: Lazarus
mesh_terms: D005434:Flow Cytometry; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology*; D007963:Leukocytes, Mononuclear / Q000201:enzymology*; D010750:Phosphoproteins / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D012680:Sensitivity and Specificity; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000097:blood / Q000276:immunology / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human