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B Activity and Apoptosis in Chronic Lymphocytic Leukemia B Cells1
,
Divisions of
*
Hematology-Oncology and
Allergy and Immunology, Department of Medicine, Weill Medical College and
Program in Immunology, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021
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-
B 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-B activity by electrophoretic
mobility shift assay. We consistently observed high levels of nuclear
NF-B-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-B activity and prolonged CLL cell
survival in vitro. The principle NF-B 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-B
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-B 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.
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