Defects of beta 2-adrenergic signal transduction in chronic lymphocytic leukaemia: relationship to disease progression.

Abstract

The second messenger 3':5'-cyclic adenosine monophosphate (cAMP) inhibits the proliferation of human B lymphocytes. In lymphoid malignancies, cAMP levels or the number of beta 2-adrenergic receptors seem to be decreased. In order to explore this phenomenon further, the function of the beta 2-adrenergic receptor complex was examined in mononuclear leucocytes (MNLs) from patients with B-cell chronic lymphocytic leukaemia (CLL). Peripheral blood MNLs from 25 CLL patients (16 male, nine female: aged 62 +/- 9 years) and 10 healthy volunteers (seven male, three female; aged 47 +/- 19 years) were used. The binding characteristics of beta 2-adrenergic receptors (beta 2-AR) on MNLs were determined by radioligand binding assays with [125I]-cyanopindolol ([125I]-CYP). The number of high-affinity binding sites for [125I]-CYP was significantly lower in CLL patients (313 +/- 300 sites per cell; mean +/- SD) than in control subjects (1479 +/- 1268 sites per cell). Moreover, the density of beta 2-AR decreased with disease progression, from Binet stage A (371 +/- 236, n = 13) to B (236 +/- 136, n = 7) and C (141 +/- 59, n = 5) (P < 0.05; Kruskal-Wallis analysis). Functional analyses of the beta 2-AR complex were performed by measuring the cellular cAMP content of MNLs in response to different stimulators. The cAMP production of MNLs upon isoprenaline stimulation (ISO; 10 min, 10(-4) mol L-1) was slightly lower in CLL patients (12.5 +/- 7.04 pmol 10(-6) cells) than in control subjects (15.91 +/- 10.08 pmol 10(-6) cells), and decreased with CLL progression (stage A 14 +/- 7; stage B 13.66 +/- 3.91; stage C 3.07 +/- 0.79 pmol 10(-6) cells). In contrast, cAMP accumulation in response to cholera toxin (CHO; 10(-4) gml-1, 120 min) was not different in control subjects (70.07 +/- 31.30 pmol 10(-6) cells) and CLL patients (stage A 95.24 +/- 123.07, stage B 70.76 +/- 57.37, stage C 33.21 +/- 33.73 pmol 10(-6) cells). When stimulated with forskolin (100 mumol L-1, 15 min), control MNLs produced about ten-fold more cAMP than CLL MNLs (188.56 +/- 92.53 vs. 17.88 +/- 10.32 pmol 10(-6) cells); this response was not stage dependent. Taken together, the results show that the beta 2-AR transmembrane signalling is impaired in CLL patients. The correlation of some beta 2-AR signalling defects with disease progression suggests that they may contribute to the disease progression of CLL patients.