Epigenetic regulation of Wnt-signaling pathway in acute lymphoblastic leukemia

Abstract

Activation of the Wnt/␤-catenin signaling pathway is a hallmark of a number of solid tumors. We analyzed the regulation of the Wnt/␤-catenin pathway in acute lymphoblastic leukemia (ALL) and its role in the pathogenesis of the disease. We found that expression of the Wnt inhibitors sFRP1, sFRP2, sFRP4, sFRP5, WIF1, Dkk3, and Hdpr1 was down-regulated due to abnormal promoter methylation in ALL IntroductionThe evolutionarily conserved Wnt-signaling pathway has pivotal roles during the development of many organ systems. Central to this pathway is a multiprotein scaffold consisting of adenomatous polyposis coli (APC), glycogen synthase kinase (GSK)-3␤, axin, and the transcriptional cofactor ␤-catenin. In the absence of Wnt ligands, ␤-catenin levels are kept low through constitutive phosphorylation by GSK-3␤, which leads to the ubiquitination and degradation of ␤-catenin. 1-3 Binding of the Wnt ligands to their receptors, Frizzled (Fz), leads to activation of the adaptor protein, Disheveled (Dvl), and the inhibition of GSK-3␤ activity, reducing phosphorylation and subsequent degradation of ␤-catenin. ␤-Catenin is stabilized and translocates to the nucleus where it binds members of the T-cell factor (Tcf)/lymphoid-enhancing factor (Lef) family of transcription factors and induces the expression of target gene such as CMYC and Cyclin D1. 4 This signaling pathway is controlled by a number of natural Wnt antagonists that interfere with ligand-receptor interactions or Dvl protein, including members of the Dickkopf (DKK) family, the secreted Frizzled-related protein (sFRP) family, the Wnt inhibitory factor-1 (WIF1), and the human Dapper protein-1 (HDPR1).Recent studies have demonstrated a role for Wnt signal transduction at several stages of lymphocyte development and in the self-renewal of hematopoietic stem cells. 5,6 All of them indicate a crucial role for the Wnt-signaling pathway in the proliferation of thymocytes and also of pro-B cells, suggesting that Wnt proteins can function as growth factors for progenitor cells of both the Band T-cell lineages. 4,7,8 Abnormal Wnt signaling has become a hallmark of some types of solid tumors, most notably colon and hepatocellular carcinomas, 9,10 and has been commonly associated with mutations in the amino-terminal region of ␤-catenin that make the molecule resistant to processing through the degradation pathway or in other proteins in this pathway, like the APC gene. 11 In addition, the functional loss of Wnt antagonists can contribute to activation of the Wnt pathway and result in carcinogenesis through deregulation of cell proliferation and differentiation. Recent studies have shown that impaired regulation of Wnt-antagonists such as sFRP, WIF1, HDPR1, and DKK3 by promoter hypermethylation is present in several human malignancies. [12][13][14][15][16][17] Given that Wnt signals are important for the survival and expansion of lymphocyte progenitors, it has been suggested that dysregulated Wnt signaling could be a mechanism underlying lymphoid leukemogenesis. Recent studies in...

In vitro study of the effects of ELF electric fields on gene expression in human epidermal cells

“…Several papers concerning this subject indicate an activation of the Wnt signaling pathway in ALL [Khan et al, 2007] and an increase in the concentration of β-catenin [Chung et al, 2002]. Other articles showed inhibition of the Wnt signaling pathway as "an attractive target for the use of more specific therapies…" [Román-Gómez, 2007]. In our results, the β-catenin (present in the Wnt signaling pathway) and the Wnt signaling pathway are inhibited by the increased expression of the gene responsible for the synthesis of DKK1.…”

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

“…Importantly, the expression of leading edge genes from the rapamycin-response signature in T-ALL diagnostic specimens could predict patient outcome; the same was true of the gene signatures associated with ex vivo DEX resistance, demonstrating the clinical relevance of this previously described signature . The Connectivity Map analysis also associated the polyphenol antioxidants resveratrol and quercetin with GC resistance, compounds that have been shown to inhibit proliferation and induce apoptosis in a variety of cancer cell types (Mertens-Talcott and Percival, 2005;Zunino and Storms, 2006;Roman-Gomez et al, 2007). The ability of these agents to enhance GC cytotoxicity, together with their favourable toxicity profile (they are abundant in everyday foods), reinforces the case for inclusion of such compounds in ALL therapeutic trials.…”

Preclinical activity of LBH589 alone or in combination with chemotherapy in a xenogeneic mouse model of human acute lymphoblastic leukemia

“…Similarly, ALL-B1 cells from mice treated with LBH589 clustered separately from untreated samples showing 217 genes hypomethylated and 54 hypermethylated genes (Figure 4 and Supplementary Table S2). As an example, genes that are known to be hypermethylated in ALL such as the Wnt inhibitor SFRP4 involved in WNT pathway 11 became hypomethylated after treatment with LBH589. Finally, treatment with LBH589 and vincristine --dexamethasone prolonged survival of the leukemic mice in comparison with the control animals (Po0.05).…”