Clonal heterogeneity in chronic lymphocytic leukemia cells: Superior response to surface IgM cross-linking in CD38, ZAP-70-positive cells

Giovanna Cutrona, Monica Colombo, Serena Matis, Marina Fabbi, Mauro Spriano, Vincenzo Callea, Ernesto Vigna, Massimo Gentile, Simonetta Zupo, Nicholas Chiorazzi, Fortunato Morabito, Manlio Ferrarini

Research output: Contribution to journalArticlepeer-review


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. Design and 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.

Original languageEnglish
Pages (from-to)413-422
Number of pages10
Issue number3
Publication statusPublished - Mar 2008


  • Apoptosis
  • CD38
  • Chronic lymphocytic leukemia
  • Signal transduction
  • ZAP-70

ASJC Scopus subject areas

  • Hematology


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