Abstract
BackgroundB cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common paediatric cancer. BCP-ALL blasts typically retain wild type p53, and are therefore assumed to rely on indirect measures to suppress transformation-induced p53 activity. We have recently demonstrated that the second messenger cyclic adenosine monophosphate (cAMP) through activation of protein kinase A (PKA) has the ability to inhibit DNA damage-induced p53 accumulation and thereby promote survival of the leukaemic blasts.Development of BCP-ALL in the bone marrow (BM) is supported by resident BM-derived mesenchymal stromal cells (MSCs). MSCs are known to produce prostaglandin E2 (PGE2) which upon binding to its receptors is able to elicit a cAMP response in target cells. We hypothesized that PGE2 produced by stromal cells in the BM microenvironment could stimulate cAMP production and PKA activation in BCP-ALL cells, thereby suppressing p53 accumulation and promoting survival of the malignant cells.MethodsPrimary BCP-ALL cells isolated from BM aspirates at diagnosis were cocultivated with BM-derived MSCs, and effects on DNA damage-induced p53 accumulation and cell death were monitored by SDS-PAGE/immunoblotting and flow cytometry-based methods, respectively. Effects of intervention of signalling along the PGE2-cAMP-PKA axis were assessed by inhibition of PGE2 production or PKA activity. Statistical significance was tested by Wilcoxon signed-rank test or paired samples t test.ResultsWe demonstrate that BM-derived MSCs produce PGE2 and protect primary BCP-ALL cells from p53 accumulation and apoptotic cell death. The MSC-mediated protection of DNA damage-mediated cell death is reversible upon inhibition of PGE2 synthesis or PKA activity. Furthermore our results indicate differences in the sensitivity to variations in p53 levels between common cytogenetic subgroups of BCP-ALL.ConclusionsOur findings support our hypothesis that BM-derived PGE2, through activation of cAMP-PKA signalling in BCP-ALL blasts, can inhibit the tumour suppressive activity of wild type p53, thereby promoting leukaemogenesis and protecting against therapy-induced leukaemic cell death. These novel findings identify the PGE2-cAMP-PKA signalling pathway as a possible target for pharmacological intervention with potential relevance for treatment of BCP-ALL.
Highlights
B cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common paediatric cancer
We have previously demonstrated that elevated levels of cyclic adenosine monophosphate can suppress DNA damage-induced p53 accumulation by promoting the interaction between p53 and its negative regulator HDM2, thereby attenuating the resulting cell death in BCP-ALL blasts [9,10,11]. cAMP is an important physiological signal transducer in lymphocytes [12,13,14], and it is generated by adenylate cyclase (AC) upon ligand binding to a subgroup of G proteincoupled receptors (GPCRs) activating the stimulatory alpha subunit Gαs
Cocultivation with Mesenchymal stromal cell (MSC) protects primary BCP-ALL cells from cell death Previous work from our group demonstrated that prostaglandin E2 (PGE2), a naturally occurring eicosanoid secreted by the bone marrow microenvironment (BMME), could replicate the effects of augmented cAMP levels to inhibit basal and DNA damage-induced p53 levels and cell death in primary BCP-ALL blasts [9,11]
Summary
B cell precursor acute lymphoblastic leukaemia (BCP-ALL) is the most common paediatric cancer. We hypothesized that PGE2 produced by stromal cells in the BM microenvironment could stimulate cAMP production and PKA activation in BCP-ALL cells, thereby suppressing p53 accumulation and promoting survival of the malignant cells. Relapses occur in children with standard risk features, accounting for more than a third of the total BCP-ALL-associated death toll [2]. It is well-documented that survivors experience a wide range of serious long-term treatment-associated side effects such as secondary cancers, chronic organ damage, cognitive, and psychosocial difficulties [4,5,6,7], emphasizing the need for further improvement of treatment strategies
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