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Richard R Furman, Zahra Asgary, John O Mascarenhas, Hsiou-Chi Liou, Elaine J Schattner, Modulation of NF-κB Activity and Apoptosis in Chronic Lymphocytic Leukemia B Cells, The Journal of Immunology, Volume 164, Issue 4, February 2000, Pages 2200–2206, https://doi.org/10.4049/jimmunol.164.4.2200
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Abstract
Chronic lymphocytic leukemia (CLL) is an indolent malignancy of CD5+ B lymphocytes. CLL cells express CD40, a key regulator of B cell proliferation, differentiation, and survival. In nonmalignant B cells, CD40 ligation results in nuclear translocation and activation of NF-κB proteins. Based on observations that in some CLL cases, the tumor cells express both CD40 and its ligand, CD154 (CD40 ligand), we proposed a model for CLL pathogenesis due to CD40 ligation within the tumor. To evaluate this issue, we used freshly isolated CLL B cells to examine constitutive and inducible NF-κB activity by electrophoretic mobility shift assay. We consistently observed high levels of nuclear NF-κB-binding activity in unstimulated CLL B cells relative to that detected in nonmalignant human B cells. In each case examined, CD40 ligation further augmented NF-κB activity and prolonged CLL cell survival in vitro. The principle NF-κB proteins in stimulated CLL cells appear to be quite similar to those in nonmalignant human B cells and include p50, p65, and c-Rel. In a CD154-positive case, blocking CD154 engagement by mAb to CD154 resulted in inhibition of NF-κB activity in the CLL cells. The addition of anti-CD154 mAb resulted in accelerated CLL cell death to a similar degree as was observed in cells exposed to dexamethasone. These data indicate that CD40 engagement has a profound influence on NF-κB activity and survival in CLL B cells, and are consistent with a role for CD154-expressing T and B cells in CLL pathogenesis. The data support the development of novel therapies based on blocking the CD154-CD40 interaction in CLL.
