Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia

Ng, Ozden Hatirnaz; Erbilgin, Yücel; Fırtına, Sinem; Çelkan, Tiraje; Karakaş, Zeynep; Aydoğan, Gönül; Türkkan, Emine; Yıldırmak, Yıldız; Timur, Çetin; Zengin, Emine; Dongen, Jacques J. M. van; Staal, Frank J. T.; Özbek, Uğur; Sayitoğlu, Müge

doi:10.1038/bcj.2014.12

Cited by 61 publications

(78 citation statements)

References 43 publications

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“…In adult human mesenchymal stem cells from bone marrow stoma, high levels of DKK1 allow the cells to reenter the cell cycle by inhibiting the canonical WNT pathway (19). In our previous study, deregulated WNT/β-catenin signaling was shown as a novel oncogenic event in childhood T-ALL (20), whereas this is not the case for B-ALL patients (unpublished data). Here, DKK1 expression was not significant in T-ALL, supporting our previous findings due to the canonical WNT inhibitor role of DKK1.…”

Section: Discussionmentioning

confidence: 94%

Dysregulation of the DKK1 gene in pediatric B-cell acute lymphoblastic leukemia

Fırtına¹,

Ng²,

Erbilgin³

et al. 2017

Turk J Med Sci

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Background/aim: The canonical Wingless-type (WNT) pathway is involved in normal hematopoietic cell development and deregulated WNT signaling is implicated in the development of hematological malignancies. Dickkopf 1 (DKK1) acts as a modulator of the β-catenin regulated canonical pathway. Activation of DKK1 leads to apoptosis and growth suppression, whereas silencing by promoter hypermethylation results in abnormal WNT activation. The secreted inhibitor Dickkopf can antagonize WNT signaling by competitively binding to low density lipoprotein receptors (LRPs) 5 and 6. Materials and methods:We studied DKK1 gene promoter methylation and investigated DKK1, β-catenin, LRP5, and LRP6 mRNA levels in B-cell acute lymphoblastic leukemia (B-ALL) patients (n = 90). Methylation-specific PCR and bisulfite sequencing were used for methylation profiling and quantitative real-time PCR was used for mRNA detection. Results:The DKK1 gene was examined for its promoter methylation and only 33% of patients were found methylated. On the other hand, B-ALL cases showed high expression of DKK1 (P = 0.01), LRP5 (P = 0.04), and LRP6 (P = 0.02) compared to normal bone marrow cells. Conclusion:DKK1 methylation exists in some of cases but is not sufficient for WNT pathway activation alone in pediatric B-ALL.

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Section: Discussionmentioning

confidence: 94%

Dysregulation of the DKK1 gene in pediatric B-cell acute lymphoblastic leukemia

Fırtına¹,

Ng²,

Erbilgin³

et al. 2017

Turk J Med Sci

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“…[36][37][38] Here, we employed the small molecule tankyrase inhibitor XAV-939 that enhances b-catenin turnover by stabilizing AXIN. 39 XAV-939 showed efficacy against human T-ALL cell lines in vitro in a dose-dependent manner and modest synergy in combination with a g-secretase inhibitor that blocks Notch signaling ( Figure 6B-C).…”

Section: Antagonizing Wnt Signaling In Human T-allmentioning

confidence: 99%

Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling

Giambra

Jenkins

Lam

et al. 2015

Blood

108

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“…Constitutive activation of NOTCH and β-catenin-mediated WNT signaling pathways are two of the most important and common alternations found in T-ALL [35, 36], and c-Myc is the direct transcriptional target of both pathways. In this study, we showed that DEX could inhibit both c-Myc and β-catenin expressions in GC- sensitive CEM-C7 cells, but not in GC-resistant CEM-C1 cells.…”

Section: Discussionmentioning

confidence: 99%

Antileukemia Effect of Ciclopirox Olamine Is Mediated by Downregulation of Intracellular Ferritin and Inhibition β-Catenin-c-Myc Signaling Pathway in Glucocorticoid Resistant T-ALL Cell Lines

Liu

et al. 2016

PLoS ONE

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Ciclopirox olamine (CPX) is an antifungal drug that has been reported to have antitumor effects. In this study we investigated the antileukemia effects and the possible mechanisms of CPX on glucocorticoid (GC)-resistant T-cell acute lymphoblastic leukemia (T-ALL) cell lines. The results indicated that CPX inhibited the growth of GC-resistant T-ALL cells in a time- and dose-dependent manner, and this effect was closely correlated with the downregulation of intracellular ferritin. CPX induced cell cycle arrest at G1 phase by upregulation of cyclin-dependent kinase (CDK) inhibitor of p21 and downregulation of the expressions of cyclin D, retinoblastoma protein (Rb), and phosphorylated Rb (pRb). CPX also enhanced apoptotic cell death by downregulation of anti-apoptotic proteins such as Bcl-2, Bcl-xL, and Mcl-1. More importantly, CPX demonstrated a strong synergistic antileukemia effect with GC and this effect was mediated, at least in part, by inhibition of the β-catenin-c-Myc signaling pathway. These findings suggest that CPX could be a promising antileukemia drug, and modulation of the intracellular ferritin expression might be an effective method in the treatment of ALL. Therefore, integrating CPX into the current GC-containing ALL protocols could lead to the improvement of the outcome of ALL, especially GC-resistant ALL.

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Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia

Cited by 61 publications

References 43 publications

Dysregulation of the DKK1 gene in pediatric B-cell acute lymphoblastic leukemia

Dysregulation of the DKK1 gene in pediatric B-cell acute lymphoblastic leukemia

Leukemia stem cells in T-ALL require active Hif1α and Wnt signaling

Antileukemia Effect of Ciclopirox Olamine Is Mediated by Downregulation of Intracellular Ferritin and Inhibition β-Catenin-c-Myc Signaling Pathway in Glucocorticoid Resistant T-ALL Cell Lines

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