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Defects of beta 2-adrenergic signal transduction in chronic lymphocytic leukaemia: relationship to disease
1Städtisches Krankenhaus München-Schwabing, I, Universität München, Germany.
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.
Insights
The beta 2-adrenergic receptor (beta 2-AR) signaling pathway is impaired in B-cell chronic lymphocytic leukemia (CLL) patients. Reduced beta 2-AR density and function correlate with CLL progression, suggesting a role in disease advancement.
Area of Science:
- Immunology
- Cellular Biology
- Oncology
Background:
- The second messenger cyclic adenosine monophosphate (cAMP) inhibits human B lymphocyte proliferation.
- Lymphoid malignancies are often associated with decreased cAMP levels or beta 2-adrenergic receptor (beta 2-AR) numbers.
- Understanding beta 2-AR function in B-cell chronic lymphocytic leukemia (CLL) is crucial for exploring disease mechanisms.
Purpose of the Study:
- To investigate the function of the beta 2-adrenergic receptor complex in mononuclear leucocytes (MNLs) from CLL patients.
- To determine the density and binding characteristics of beta 2-AR on MNLs in CLL.
- To analyze the cellular cAMP content in response to beta 2-AR stimulation in CLL patients.
Main Methods:
- Radioligand binding assays using [125I]-cyanopindolol ([125I]-CYP) to quantify beta 2-AR binding sites on MNLs.
- Measurement of cellular cAMP levels in MNLs upon stimulation with isoprenaline (ISO), cholera toxin (CHO), and forskolin.
- Comparison of beta 2-AR density and cAMP production between CLL patients and healthy controls, stratified by Binet stage.
Main Results:
- CLL patients exhibited significantly lower numbers of high-affinity beta 2-AR binding sites compared to controls.
- Beta 2-AR density decreased progressively with advancing Binet stages (A to C) in CLL patients.
- While isoprenaline-stimulated cAMP production was slightly reduced and decreased with stage, forskolin-stimulated cAMP production was markedly lower in CLL patients, indicating impaired beta 2-AR transmembrane signaling.
Conclusions:
- The beta 2-adrenergic receptor transmembrane signaling pathway is impaired in B-cell chronic lymphocytic leukemia.
- The observed defects in beta 2-AR signaling correlate with disease progression, suggesting a potential role in CLL advancement.
- These findings highlight the importance of beta 2-AR function in the context of CLL pathogenesis.