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B lymphocytes from chronic lymphocytic leukaemia (B-CLL) patients express the two CD23 isoforms (type A and B), which differ only in their intracytoplasmic domain. The abnormal regulation of the CD23 antigen in response to IL-4, IFNs alpha and gamma results in CD23 over-expression on B-CLL cells. Our present study shows that the two CD23 isoforms are differentially and abnormally regulated on B-CLL cells. IL-4 selectively up-regulates CD23 type A mRNA in five different B-CLL patients, whereas in normal B cells it enhances CD23 type A and is the most potent inducer of type B. In contrast, phorbol esters (PMA) up-regulate both CD23 isoforms in the malignant B cells and specifically increases type B in normal B cells. We next postulated that cytokines other than IL-4 regulate CD23 B isoform in B-CLL cells and therefore examined the effect of IL-2, IFN-gamma and IFN-alpha. We found that the ability of a given cytokine to induce B-CLL growth (i.e. IL-2 and IFN alpha) is concurrent with a selective up-regulation of CD23 type B mRNA, whereas lymphokines that have no B cell growth activity (i.e. IL-4 and IFN-gamma) specifically increase CD23 type A mRNA. We next showed that IL-4 and IFN gamma prevent hydrocortisone-induced programmed cell death and that the rescued malignant B cells mainly express CD23 type A. Given that CD23 molecule has been reported to play a role in normal B cell proliferation and survival, it is therefore proposed that in B-CLL cells the expression of CD23 type A may be related to cell viability and that of type B to cell proliferation. These data suggest that the CD23 molecule may contribute to the physiopathology of the disease which is characterized by the accumulation of long-lived and slow-dividing monoclonal B cells.

The role of cytokines in the growth and spreading of human hematologic malignancies has been underlined in recent years. Here we report evidence that a human 12-kDa B cell growth factor (BCGF-12KD) may function as a growth stimulatory factor in B cell chronic lymphocytic leukemia (B-CLL). First, recombinant BCGF-12KD induced dose-dependent DNA synthesis in neoplastic B cells of four B-CLL patients tested. Second, seven different B-CLL clones secreted a BCGF-12KD-like product that accounted for their proliferation. A neutralizing monoclonal antibody (mAb; Ac8) directed against a BCGF-12KD synthetic peptide inhibited the spontaneous growth of the leukemic B cells. The same mAb blocked DNA synthesis in normal tonsillar B lymphocytes induced by the culture supernatant of spontaneously proliferating B-CLL cells. Finally, BCGF-12KD mRNA was expressed in freshly isolated (two of three patients) as well as in vitro proliferating B-CLL cells (three of three patients). These findings strongly suggest that BCGF-12KD can modulate the growth of B-CLL cells in vivo as well as in vitro. They may offer significant insights into the biology of this frequent B lymphoproliferative disorder.