A crosstalk between the Wnt and the adhesion-dependent signaling pathways governs the chemosensitivity of acute myeloid leukemia

Abstract

Relapses following chemotherapy are a major hindrance to patients' survival in acute myeloid leukemia (AML). To investigate the role of the hematopoietic niche in the chemoresistance of leukemic cells, we examined two pathways: one mediated by adhesion molecules/integrins, and the other by soluble factors of the morphogen Wnt pathway. In our study, both the adhesion of leukemic blasts to fibronectin and the addition of Wnt antagonists induced, independently, resistance of AML cells to daunorubicin in a cell survival assay. Using pharmacological inhibitors and siRNA, we showed that both resistance pathways required the activity of the glycogen synthase kinase 3b (GSK3b). Moreover, the AML cell protection downstream of GSK3b was mediated by NF-jB. A link between the adhesion and the Wnt pathway was found, as adhesion of U937 on human osteoblasts, a component of the hematopoietic niche, triggered the secretion of the Wnt antagonist sFRP-1 and supported resistance to daunorubicin. The osteoblast-conditioned medium could also confer chemoresistance to U937 cells cultured in suspension, and this cell protective effect was abrogated after depletion of sFRP-1. In the context of this potential double in vivo resistance, modulators of the common signal GSK3b and of its target NF-jB could represent important novel therapeutic tools.

Glycogen synthase kinase-3: a new therapeutic target in renal cell carcinoma

“…Moreover, we show that inhibition of GSK-3 sensitised kidney cancer cells to Docetaxel suggesting that GSK-3 might contribute to renal cancer chemoresistance. Our findings are supported by another study showing that GSK-3b positively regulates NF-kBmediated chemoresistance in acute myeloid leukaemia (De Toni et al, 2006). Recently, it has been shown that GSK-3b inhibition enhanced Sorafenib-induced apoptosis in melanoma cells (Panka et al, 2008).…”

The emerging role of Wnt signaling in the pathogenesis of acute myeloid leukemia

“…Thus, Wnt5a appears to inhibit proliferation of hematopoietic cells and might function as a tumor suppressor in hematopoietic tissue. The hypothesis that Wnt signals not only contribute to proliferation and self-renewal in AML but partially also function as tumor suppressors is further supported by a study of de Toni et al 141 This group was able to show that addition of different antagonists of the canonical Wnt/ b-catenin pathway, such as sFRP-1, Dkk-1 and Wnt5a to AML blasts or U937 cells induced resistance to daunorubicin, whereas incubation with the Wnt agonist Wnt3a increased chemosensitivity. Drug resistance mediated by sFRP-1 required GSK3b and nuclear factor-kB (NF-kB) suggesting a crosslink between Wnt signaling and NF-kB activation in AML.…”

“…Drug resistance mediated by sFRP-1 required GSK3b and nuclear factor-kB (NF-kB) suggesting a crosslink between Wnt signaling and NF-kB activation in AML. 141 Osteoblasts that play a key role in the maintenance of the hematopoietic niche were shown to support drug resistance of U937 cells adhering onto osteoblasts by triggering sFRP-1 secretion. 141 As a consequence Wnt proteins seem not only to support selfrenewal and proliferation of AML cells but can also partially act as tumor suppressors and chemosensitizers.…”

“…141 Osteoblasts that play a key role in the maintenance of the hematopoietic niche were shown to support drug resistance of U937 cells adhering onto osteoblasts by triggering sFRP-1 secretion. 141 As a consequence Wnt proteins seem not only to support selfrenewal and proliferation of AML cells but can also partially act as tumor suppressors and chemosensitizers. This controversy might be closely related to the effects of Wnt signaling on specific target cells.…”

Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia

“…GSK-3b activity seems also important for adhesion and Wnt-pathway b-catenin expression and drug resistance in AML cells. 142,143 b-Catenin expression in AML cells predicts enhanced clonogenic capacities and is associated with a poor prognosis. 143 Thus, GSK-3b also plays key roles in regulating proliferative loops involved in malignant transformation of hematopoietic cells.…”