title: Analysis of signal transduction in B chronic lymphocytic leukemia cells.
abstract: 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.
mesh_terms: D000912:Antibodies, Neoplasm / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D000001:Calcimycin / Q000494:pharmacology; D004357:Drug Synergism; D004789:Enzyme Activation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015847:Interleukin-4; D007378:Interleukins / Q000494:pharmacology; D007945:Leukemia, Lymphoid / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000032:analysis; D015375:Receptors, Interleukin-2; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000912:Antibodies, Neoplasm; D007376:Interleukin-2; D007378:Interleukins; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D011971:Receptors, Immunologic; D015375:Receptors, Interleukin-2; D015847:Interleukin-4; D000001:Calcimycin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate