Defects of β₂‐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.

Promoter Polymorphisms in the β-2 Adrenergic Receptor Are Associated With Drug-Induced Gene Expression Changes and Response in Acute Lymphoblastic Leukemia

“…We observed a ninefold lower level of ADRB2 expression after in vivo treatment in the leukemia cells of patients who ultimately experienced a relapse. Consistent with this finding, a lower density of ADRB2s in chronic lymphocytic leukemia cells has been associated with disease progression, 28 and ADRB2 inhibition leads to cell invasion and transformation of benign prostate cells. 29 Furthermore, ADRB2 has been linked to apoptosis in lymphoid tissue, via two mechanisms.…”

Nerve Driven Immunity: Noradrenaline and Adrenaline

“…A decreased number of b-ARs involved in cell proliferation was described also on the T cell lymphoma BW5147 (Cremaschi et al 2000). Impaired AR expression in circulating cells from patients with chronic lymphocytic leukemia was shown to be specific for b 2 -ARs and to be associated with disease progression (Kamp et al 1997). Whether activation of b-ARs may represent a therapeutic strategy in leukemias remains however to be established.…”

The role of G protein-coupled receptors in lymphoid malignancies

“…For example, tachykinin receptor TACR1 mRNA is overexpressed in CLL patient cells compared to normal B lymphocytes and expression is higher in aggressive IGHV-unmutated CLL compared to indolent IGHV-mutated CLL [41]. Conversely, CLL mononuclear leukocytes contain fewer beta-2 adrenergic receptors (ADRB2) than healthy cells and increased dysfunction of the receptor complex is correlated with disease progression [52]. ADRB2 agonists have been shown to induce apoptotic cell death in CLL cells alone and synergistically with other agents [53] and expression of alpha-2 adrenergic receptors has also been described in CLL [54].…”