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Blood, 15 February 2002, Vol. 99, No. 4, pp. 1314-1319
NEOPLASIA
The chimeric anti-CD20 antibody rituximab induces apoptosis in
B-cell chronic lymphocytic leukemia cells through a p38 mitogen
activated protein-kinase-dependent mechanism
Irene Munk Pedersen,
Anne
Mette Buhl,
Pia Klausen,
Christian H. Geisler, and
Jesper Jurlander
From the Leukemia Laboratory, Department of Hematology,
The Finsen Centre, Rigshospitalet, Copenhagen, Denmark.
Antibodies against CD20 can activate complement and induce
antibody-dependent cellular cytotoxicity (ADCC) in B lymphocytes. In
B-cell lines, such antibodies also induce apoptosis. In this study, the
expression and function of CD20 on B-cell chronic lymphocytic leukemia
(B-CLL) cells were analyzed. Flow cytometric analysis demonstrated that B-CLL cells express CD20 with a fluorescence intensity that is significantly weaker than that of normal
CD5+ and CD5 B cells and that of
malignant CD5 low-grade non-Hodgkin lymphoma cells. A
small population of cells from healthy donors that have an
expression pattern of CD5 and CD20 identical to that of B-CLL cells
were identified, and this population was confirmed to be of T lineage,
not B lineage. Culture of freshly isolated B-CLL cells in the
presence of the chimeric anti-CD20 antibody rituximab and a
cross-linking F(ab)2 fragment, resulted in dose- and
time-dependent induction of apoptosis. The induction of apoptosis
occurred under conditions in which the influence of complement
activation and ADCC was negligible. Cross-linking of rituximab induced
strong and sustained phosphorylation of the 3 mitogen activated protein
(MAP) kinases c-Jun NH2-terminal protein kinase,
extracellular signal-regulated kinase, and p38.
Introduction of the p38 inhibitor SB203580 into the system completely
blocked signaling downstream of p38, as evidenced by the absence of
MAPKAP K2 activity, and significantly reduced the degree of
anti-CD20-induced apoptosis. These results demonstrate that
cross-linking of rituximab bound to CD20 on freshly isolated B-CLL
cells induces apoptosis through a signaling pathway that is dependent
on p38 MAP-kinase activation.
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