title: ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL).
abstract: Molecular markers like IgV(H) mutational status, chromosomal abnormalities, and CD38 and ZAP-70 expression have prognostic value in B-cell chronic lymphocytic leukemia (B-CLL). These may be pathogenetic because of the coincidental expression of ZAP-70 and increased B-cell receptor (BCR) signaling and the signaling function of CD38 in CLL. This study shows that ZAP-70(+) CLL B cells respond in vitro more readily than ZAP-70(-) CLL and normal B cells to chemokine migratory signals through enhanced surface CCR7 expression (P = .009; P < .001) and increased responsiveness to its ligands CCL19 and CCL21, demonstrated by F-actin polymerization (P < .05) and cellular migration (P < .01). In addition, ZAP-70(+) CLL cells exhibit sustained ERK phosphorylation/activation following stimulation with CXCL12 (SDF1-alpha, a survival factor produced by stromal cells) compared with ZAP-70(-) cells (P = .004). Following coculture with nurse-like cells, the survival of ZAP-70(+) but not ZAP-70(-) CLL cells is significantly enhanced by the addition of CXCL12 (P < .05), an effect that is partially blocked by the MEK inhibitor PD98059. These advantageous migratory and survival responses may promote easier access to and greater proliferation in pseudo-germinal centers and explain in part the more progressive nature of ZAP-70(+) disease.
authors.affiliation: Department of Haematology Level 7, Derriford Hospital, Plymouth PL6 8DH, United Kingdom. sarah.richardson@phnt.swest.nhs.uk
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Richardson
authors.forename: Christine
authors.initials: C
authors.lastname: Matthews
authors.forename: Mark A
authors.initials: MA
authors.lastname: Catherwood
authors.forename: H Denis
authors.initials: HD
authors.lastname: Alexander
authors.forename: B Sean
authors.initials: BS
authors.lastname: Carey
authors.forename: Joanna
authors.initials: J
authors.lastname: Farrugia
authors.forename: Anne
authors.initials: A
authors.lastname: Gardiner
authors.forename: Sarah
authors.initials: S
authors.lastname: Mould
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: J Adrian
authors.initials: JA
authors.lastname: Copplestone
authors.forename: Archibald G
authors.initials: AG
authors.lastname: Prentice
mesh_terms: D016022:Case-Control Studies; D002465:Cell Movement; D002470:Cell Survival; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC / Q000494:pharmacology; D019743:Chemokines, CXC / Q000494:pharmacology; D005803:Genes, Immunoglobulin; D006801:Humans; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008954:Models, Biological; D009154:Mutation; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D015398:Signal Transduction; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism*
chemical_list: C515460:CCL19 protein, human; C515478:CCL21 protein, human; C515370:CCR7 protein, human; C515255:CXCL12 protein, human; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054377:Chemokine CXCL12; D019742:Chemokines, CC; D019743:Chemokines, CXC; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human