title: Clonal heterogeneity in chronic lymphocytic leukemia cells: superior response to surface IgM cross-linking in CD38, ZAP-70-positive cells.
abstract: BACKGROUND
  Patients with chronic lymphocytic leukemia whose cells express CD38 and ZAP-70 and utilize unmutated Ig VH region genes have a very poor prognosis. We studied whether cells expressing CD38 and ZAP-70 are more susceptible to stimulation through B-cell receptors than are cells that do not express CD38 and ZAP-70.
  
  
  METHODS
  CD38-positive and CD38-negative leukemic cells were separated from single cases and compared for their response to B-cell receptor cross-linking and ZAP-70 expression. Cohort studies were also carried out by measuring the apoptotic response to surface immunoglobulin M (IgM) cross-linking in 82 patients with chronic lymphocytic leukemia and the protein tyrosine phosphorylation induced by surface IgM in 21 patients.
  
  
  RESULTS
  CD38-positive cells, isolated from cases of chronic lymphocytic leukemia classified as CD38-positive or CD38-negative, expressed more ZAP-70 than the corresponding CD38-negative cells, exhibited more robust protein tyrosine phosphorylation and had a greater tendency to apoptosis upon B-cell receptor cross-linking. In the cohort studies, surface IgM-induced protein tyrosine phosphorylation correlated significantly with CD38 and ZAP-70 expression and with the absence of Ig VH gene mutations. Apoptosis induced by surface IgM cross-linking correlated significantly only with the proportion of CD38-positive cells. Difficulties in finding more definitive correlations were probably related to imprecision in the in vitro test system and in the definition of cases as positive or negative.
  
  
  CONCLUSIONS
  Collectively, these data indicate that CD38-positive, ZAP-70-positive cells have a greater capacity for signaling through the B-cell receptor and suggest a function for B-cell receptor signaling in promoting chronic lymphocytic leukemia cell expansion, especially within the CD38-positive fraction of the leukemic clone.
authors.affiliation: PhD. Divisione di Oncologia Medica C Istituto Nazionale per la Ricerca sul Cancro, IST, L.go Rosanna Benzi, 10 16132 Genoa, Italy. giovanna.cutrona@istge.it
authors.forename: Giovanna
authors.initials: G
authors.lastname: Cutrona
authors.forename: Monica
authors.initials: M
authors.lastname: Colombo
authors.forename: Serena
authors.initials: S
authors.lastname: Matis
authors.forename: Marina
authors.initials: M
authors.lastname: Fabbi
authors.forename: Mauro
authors.initials: M
authors.lastname: Spriano
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Callea
authors.forename: Ernesto
authors.initials: E
authors.lastname: Vigna
authors.forename: Massimo
authors.initials: M
authors.lastname: Gentile
authors.forename: Simonetta
authors.initials: S
authors.lastname: Zupo
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: Fortunato
authors.initials: F
authors.lastname: Morabito
authors.forename: Manlio
authors.initials: M
authors.lastname: Ferrarini
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000032:analysis*; D017209:Apoptosis / Q000276:immunology; D015415:Biomarkers; D002999:Clone Cells / Q000737:chemistry / Q000276:immunology; D015331:Cohort Studies; D006801:Humans; D007075:Immunoglobulin M / Q000276:immunology*; D007152:Immunologic Capping; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000737:chemistry / Q000276:immunology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000276:immunology; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000032:analysis*
chemical_list: D015415:Biomarkers; D007075:Immunoglobulin M; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D051997:ADP-ribosyl Cyclase 1