DEFECTS OF BETA(2)-ADRENERGIC SIGNAL-TRANSDUCTION IN CHRONIC LYMPHOCYTIC-LEUKEMIA - RELATIONSHIP TO DISEASE PROGRESSION

The second messenger 3':5'-cyclic adenosine monophosphate (cAMP) inhib its 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 leuka emia (CLL). Peripheral blood MNLs from 25 CLL patients (16 male, nine female; aged 62+/-9 years) and 10 healthy volunteers (seven male, thre e female; aged 47+/-19 years) were used. The binding characteristics o f beta(2)-adrenergic receptors (beta(2)-AR) on MNLs were determined by radioligand binding assays with [I-125]-cyanopindolol ([I-125]-CYP). The number of high-affinity binding sites for [I-125]-CYP was signific antly lower in CLL patients (313+/-300 sites per cell; mean+/-SD) than in control subjects (1479+/-1268 sites per cell). Moreover, the densi ty 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 <0.0 5; Kruskal-Wallis analysis). Functional analyses of the beta(2)-AR com plex were performed by measuring the cellular cAMP content of MNLs in response to different stimulators. The cAMP production of MNLs upon is oprenaline stimulation (ISO; 10 min, 10(-4) mol L(-1)) was slightly lo wer in CLL patients (12.5+/-7.04 pmol 10(-6) cells) than in control su bjects (15.91+/-10.08 pmol 10(-6) cells), and decreased with CLL progr ession (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) g ml(-1), 120 min) was not different in control sub jects (70.07+/-31.30 pmol 10(-)6 cells) and CLL patients (stage A 95.2 4+/-123.07, stage B 70.76+/-57.37, stage C 33.21+/-33.73 pmol 10(-6) c ells). When stimulated with forskolin (100 mu mol L(-1), 15 min), cont rol 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 d ependent. Taken together, the results show that the beta(2)-AR transme mbrane 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.