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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 990-995
Triggering of CD40 Antigen Inhibits Fludarabine-Induced Apoptosis
in B Chronic Lymphocytic Leukemia Cells
Maria Fiammetta Romano,
Annalisa Lamberti,
Pierfrancesco Tassone,
Fiorella Alfinito,
Silvia Costantini,
Federico Chiurazzi,
Thierry Defrance,
Patrizio Bonelli,
Franca Tuccillo,
Maria Caterina Turco, and
Salvatore Venuta
From the Dipartimento di Biochimica e Biotecnologie Mediche,
Università Federico II, Napoli, Italia; Dipartimento di Oncologia
Sperimentale, Istituto Nazionale Tumori Napoli, Italia; Dipartimento di
Medicina Sperimentale e Clinica, Università of Reggio Calabria,
Italia; DACM area of Haematology, Università Federico II, Napoli,
Italia; and INSERM, Lyon, France.
We analyzed the effect of CD40 triggering on the
fludarabine-induced apoptosis of B chronic lymphocytic leukemia (B-CLL)
cells. Peripheral blood samples obtained from 15 patients were
incubated with fludarabine in the absence or the presence of the
anti-CD40 monoclonal antibody (MoAb) G28-5. In 12 patients a
significant proportion of apoptotic cells, ranging from 22% to 38%
(mean ± SE: 28.5 ± 1.6), were detected after 3 days of culture.
In 9 of these samples, the addition of G28-5 reduced apoptosis by at
least 30.1% and by 57.1% ± 7.8% on average
(P = .0077). Because the CD40 antigen activates NF- B/Rel
transcription factors in B cells, and NF-B/Rel complexes can inhibit
cell apoptosis, we investigated whether the antiapoptotic effect of
G28-5, in our system, could be related to modulation of NF-B/Rel
activity. As expected, B-CLL cells displayed significant levels of
nuclear NF-B/Rel activity; p50, RelA, and c-Rel components of the
NF-B/Rel protein family were identified in these complexes. After
exposure to fludarabine, NF-B/Rel complexes were decreased in the
nuclei. The addition of G28-5 upregulated the NF-B/Rel levels. To
determine the involvement of NF-B/Rel activity in the
G28-5-mediated inhibition of apoptosis, we blocked the transcription
factor with a decoy oligonucleotide, corresponding to the NF-B/Rel
consensus sequence. Cells incubated with the anti-CD40 MoAb in the
presence of the decoy oligonucleotide but not a control
oligonucleotide displayed a complete impairment of the
G28-5 antiapoptotic effect, indicating that NF-B/Rel activity was
required for the inhibition of apoptosis. These results suggest that
CD40 triggering in vivo could counteract the apoptotic effect of
fludarabine on B-CLL cells and that its neutralization, or the use of
NF-B/Rel inhibitors, could improve the therapeutic effect of
fludarabine.
© 1998 by The American Society of Hematology.
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