Cholinergic Machinery as Relevant Target in Acute Lymphoblastic T Leukemia

Abstract

Various types of non-neuronal cells, including tumors, are able to produce acetylcholine (ACh), which acts as an autocrine/paracrine growth factor. T lymphocytes represent a key component of the non-neuronal cholinergic system. T cells-derived ACh is involved in a stimulation of their activation and proliferation, and acts as a regulator of immune response. The aim of the present work was to summarize the data about components of cholinergic machinery in T lymphocytes, with an emphasis on the comparison of healthy and leukemic T cells. Cell lines derived from acute lymphoblastic leukemias of T lineage (T-ALL) were found to produce a considerably higher amount of ACh than healthy T lymphocytes. Additionally, ACh produced by T-ALL is not efficiently hydrolyzed, because acetylcholinesterase (AChE) activity is drastically decreased in these cells. Up-regulation of muscarinic ACh receptors was also demonstrated at expression and functional level, whereas nicotinic ACh receptors seem to play a less important role and not form functional channels in cells derived from T-ALL. We hypothesized that ACh over-produced in T-ALL may act as an autocrine growth factor and play an important role in leukemic clonal expansion through shaping of intracellular Ca2+ signals. We suggest that cholinergic machinery may be attractive targets for new drugs against T-ALL. Specifically, testing of high affinity antagonists of muscarinic ACh receptors as well as antagomiRs, which interfere with miRNAs involved in the suppression of AChE expression, may be the first choice options.

Heart-Rate Variability—More than Heart Beats?

“…A majority of the cells are also capable of producing ACh ( 62 ). ACh has an anti-inflammatory effect, beyond others because ACh decreases TNF production via a posttranscriptional mechanism.…”

Variation of nicotinic subtype α7 and muscarinic subtype M3 acetylcholine receptor expression in three main types of leukemia

“…The putative involvement of the non-neuronal cholinergic system in the etiology of hematopoietic derived neoplasia is of particular importance in view of various recent reports (16)(17)(18). Several studies have provided evidence demonstrating that blood cells, especially lymphocytes, possess non-neuronal cholinergic components including cholinergic AChRs (14,20).…”

“…Previous studies have shown that Jurkat, T-cell-derived leukemic cells, increased M3-mAChR expression (26). In addition, it has been proposed that high levels of ACh in T-ALL may act as an autocrine growth factor and play a significant role in leukemia T-cell clonal expansion via shaping of intracellular calcium signaling pathways (18). However, our study showed the lowest expression of both α7-nAChR and M3-mAChR was in T-ALL patients.…”

“…However, AChE activity decreased during the remission period (17). It is important to note the recent hypothesis that non-neuronal cholinergic machinery may be involved in leukemogenesis, especially in T-cell leukemia, and that its components, such as cholinergic AChRs, may represent relevant therapeutic targets for leukemia (18). To date, there has been no new information regarding the involvement of the non-neuronal cholinergic system amongst different types of leukemia.…”

Thymus-brain connections in T-cell Acute Lymphoblastic Leukemia

“…The cholinergic machinery is also present in T-ALL blasts, and a more detailed overview of this subject has been reviewed in detail by Dobrovinskaya and colleagues [26]. ACh production by T-ALL cell lines (CEM, HSB-2, Jurkat, MOLT-3, and MOLT-4) is considerably higher when compared to B-ALL cell lines and unstimulated peripheral blood mononuclear leukocytes obtained from healthy donors [23,27].…”