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, Salvatore Venuta

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Abstract

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-κB/Rel transcription factors in B cells, and NF-κB/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-κB/Rel activity. As expected, B-CLL cells displayed significant levels of nuclear NF-κB/Rel activity; p50, RelA, and c-Rel components of the NF-κB/Rel protein family were identified in these complexes. After exposure to fludarabine, NF- κB/Rel complexes were decreased in the nuclei. The addition of G28-5 upregulated the NF-κB/Rel levels. To determine the involvement of NF- κB/Rel activity in the G28-5-mediated inhibition of apoptosis, we blocked the transcription factor with a decoy oligonucleotide, corresponding to the NF-κB/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-κB/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-κB/Rel inhibitors, could improve the therapeutic effect of fludarabine.

Original languageEnglish
Pages (from-to)990-995
Number of pages6
JournalBlood
Volume92
Issue number3
Publication statusPublished - Aug 1 1998

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CD40 Antigens
B-Cell Chronic Lymphocytic Leukemia
Apoptosis
Oligonucleotides
Transcription Factors
Monoclonal Antibodies
Cells
Consensus Sequence
Therapeutic Uses
Blood
B-Lymphocytes
Modulation
fludarabine

ASJC Scopus subject areas

  • Hematology

Cite this

Romano, M. F., Lamberti, A., Tassone, P., Alfinito, F., Costantini, S., Chiurazzi, F., ... Venuta, S. (1998). Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood, 92(3), 990-995.

Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. / Romano, Maria Fiammetta; Lamberti, Annalisa; Tassone, Pierfrancesco; Alfinito, Fiorella; Costantini, Silvia; Chiurazzi, Federico; Defrance, Thierry; Bonelli, Patrizio; Tuccillo, Franca; Turco, Maria Caterina; Venuta, Salvatore.

In: Blood, Vol. 92, No. 3, 01.08.1998, p. 990-995.

Research output: Contribution to journalArticle

Romano, MF, Lamberti, A, Tassone, P, Alfinito, F, Costantini, S, Chiurazzi, F, Defrance, T, Bonelli, P, Tuccillo, F, Turco, MC & Venuta, S 1998, 'Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells', Blood, vol. 92, no. 3, pp. 990-995.
Romano MF, Lamberti A, Tassone P, Alfinito F, Costantini S, Chiurazzi F et al. Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. Blood. 1998 Aug 1;92(3):990-995.
Romano, Maria Fiammetta ; Lamberti, Annalisa ; Tassone, Pierfrancesco ; Alfinito, Fiorella ; Costantini, Silvia ; Chiurazzi, Federico ; Defrance, Thierry ; Bonelli, Patrizio ; Tuccillo, Franca ; Turco, Maria Caterina ; Venuta, Salvatore. / Triggering of CD40 antigen inhibits fludarabine-induced apoptosis in B chronic lymphocytic leukemia cells. In: Blood. 1998 ; Vol. 92, No. 3. pp. 990-995.
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AU - Costantini, Silvia

AU - Chiurazzi, Federico

AU - Defrance, Thierry

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