Published online 20 February 2008
Haematologica, Vol 93, Issue 3, 413-422 doi:10.3324/haematol.11646
Copyright © 2008 by Ferrata Storti Foundation
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Chronic Lymphocytic Leukemia

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

Giovanna Cutrona1,, Monica Colombo1, Serena Matis1, Marina Fabbi3, Mauro Spriano4, Vincenzo Callea5, Ernesto Vigna8, Massimo Gentile8, Simonetta Zupo6, Nicholas Chiorazzi7, Fortunato Morabito8, Manlio Ferrarini1,2

1 Divisione di Oncologia Medica C, Istituto Nazionale per la Ricerca sul Cancro, IST, Genova Italy
2 Dipartimento di Oncologia, Biologia e Genetica Universita’ degli Studi di Genova Italy
3 Divisione di Immunofarmacologia, Istituto Nazionale per la Ricerca sul Cancro, IST, Genova Italy
4 Dipartimento di Ematologia, Azienda Ospedaliera S. Martino, Genova Italy
5 Divisione di Ematologia, Azienda Ospedaliera Bianchi-Melacrino-Morelli, Reggio Calabria Italy
6 Divisione di Diagnostica delle Malattie Linfoproliferative, Istituto Nazionale per la Ricerca sul Cancro, IST, Genova Italy
7 Institute for Medical Research, North Shore-LIJ Health System, and Departments of Medicine, North Shore University Hospital and NYU School of Medicine, New York, USA and
8 Divisione di Ematologia, Azienda Ospedaliera di Cosenza, Cosenza, Italy

Correspondence: Giovanna Cutrona, PhD. Divisione di Oncologia Medica C Istituto Nazionale per la Ricerca sul Cancro, IST, L.go Rosanna Benzi, 10 16132 Genoa, Italy. E-mail: giovanna.cutrona{at}istge.it

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.

Key words: chronic lymphocytic leukemia, CD38, ZAP-70, signal transduction, apoptosis.