Analysis of signal transduction in B chronic lymphocytic leukemia cells
HG Drexler, MK Brenner, E Coustan-Smith, SM Gignac and AV Hoffbrand
Department of Haematology, Royal Free Hospital, London.
We report here experiments on the analysis of cellular signal transduction
in a series of patients with chronic B cell disorders (B cell chronic
lymphocytic leukemia [B-CLL] and prolymphocytic leukemia). We compared the
response of the leukemic cells with primary external signals (interleukin 2
[IL-2] or B cell differentiation factors [BCDF or IL-6]) with their
response to secondary inducers (the phorbol ester
(12-O-tetradecanoylphorbol-13-acetate [TPA] or the calcium ionophore
A23187) that circumvent the first part of the signal transduction pathway
by directly activating the key enzyme protein kinase C. One BCDF was
synthesized by mitogen-activated peripheral blood B lymphocytes; a second
BCDF was constitutively produced by the human bladder carcinoma cell line
T24. Changes in morphology, Tac (IL-2 receptor) expression, RNA synthesis
measured by 3H-uridine uptake, and immunoglobulin production tested by
enzyme-linked immunosorbent assay were used as parameters of successful
signal transduction. TPA alone and TPA plus A23187 (synergistically)
effectively initiated differentiation in all the leukemia cases. Neither
IL-2 nor BCDF (singly or in combinations) caused equivalent responses. On
the other hand, IL-2 and BCDF produced a substantial differentiation effect
on normal B lymphocytes. Our data suggest that (a) B-CLL cells are able to
respond to direct stimulation of the second messenger pathway (through
protein kinase C) but not to the physiological stimuli IL-2 or BCDF; (b)
the defect in signal transduction appears to be located upstream of protein
kinase C (a possible candidate is a G protein); (c) malignant B cells may
spontaneously or after treatment with inducers express the IL- 2 receptor
(Tac antigen) in the absence of a functional differentiating response to
IL-2; and (d) signs of proliferation/differentiation in B- CLL samples
after incubation with IL-2 or BCDF might be due to contamination of the
cell populations with residual normal B cells.
Volume 71,
Issue 5,
pp. 1461-1469,
05/01/1988
Copyright © 1988 by The American Society of Hematology
