title: SLP76 integrates into the B-cell receptor signaling cascade in chronic lymphocytic leukemia cells and is associated with an aggressive disease course.
abstract: I In the last decade, the B-cell receptor has emerged as a pivotal stimulus in the pathogenesis of chronic lymphocytic leukemia, and a very feasible therapeutic target in this disease. B-cell receptor responsiveness in chronic lymphocytic leukemia cells is heterogeneous among patients and correlates with aggressiveness of the disease. Here we show, for the first time, that SLP76, a key scaffold protein in T-cell receptor signaling, is ectopically expressed in chronic lymphocytic leukemia cells, with variable levels among patients, and correlates positively with unmutated immunoglobulin heavy chain variable gene status and ZAP-70 expression. We found that SLP76 was functionally active in chronic lymphocytic leukemia cells. A SYK-dependent basal level of phosphorylated SLP76 exists in the cells, and upon B-cell receptor engagement, SLP76 tyrosine phosphorylation is significantly enhanced concomitantly with increased physical association with BTK. B-cell receptor-induced SLP76 phosphorylation is mediated by upstream signaling events involving LCK and SYK. Knockdown of SLP76 in the cells resulted in decreased induction of BTK, PLCγ2 and IκB phosphorylation, as well as cell viability after B-cell receptor activation with anti-IgM. Consistent with our biochemical findings, high total SLP76 expression in chronic lymphocytic leukemia cells correlated with a more aggressive disease course.
  
  
  
  SLP76 is ectopically expressed in chronic lymphocytic leukemia cells where it plays a role in B-cell receptor signaling.
authors.affiliation: Department of Hematology, Tel-Aviv Sourasky Medical Center, Jerusalem, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Jerusalem, Israel.
authors.forename: Nili
authors.initials: N
authors.lastname: Dezorella
authors.affiliation: Department of Hematology, Tel-Aviv Sourasky Medical Center, Jerusalem, Israel.|Sackler Faculty of Medicine, Tel-Aviv University, Jerusalem, Israel.
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Katz
authors.affiliation: Department of Hematology, Tel-Aviv Sourasky Medical Center, Jerusalem, Israel.
authors.forename: Mika
authors.initials: M
authors.lastname: Shapiro
authors.affiliation: Department of Hematology, Hadassah University Hospital and Hebrew University Medical School, Jerusalem, Israel.
authors.forename: Aaron
authors.initials: A
authors.lastname: Polliack
authors.affiliation: Department of Hematology, Tel-Aviv Sourasky Medical Center, Jerusalem, Israel.
authors.forename: Chava
authors.initials: C
authors.lastname: Perry
authors.affiliation: Department of Hematology, Tel-Aviv Sourasky Medical Center, Jerusalem, Israel yairh@tlvmc.gov.il.|Sackler Faculty of Medicine, Tel-Aviv University, Jerusalem, Israel.
authors.forename: Yair
authors.initials: Y
authors.lastname: Herishanu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D011485:Protein Binding; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction; D000072377:Syk Kinase / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D007143:Immunoglobulin Heavy Chains; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; C092947:SLP-76 signal Transducing adaptor proteins; C000606896:SYK protein, human; D000072377:Syk Kinase; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human