Hypermethylation of Wnt antagonist gene promoters and activation of Wnt pathway in myelodysplastic marrow cells

Masala, Erico; Valencia, Ana; Buchi, Francesca; Nosi, Daniele; Spinelli, Elena; Gozzini, Antonella; Sassolini, Francesca; Sanna, Alessandro; Zecchi, Sandra; Bosi, Alberto

doi:10.1016/j.leukres.2012.05.023

Cited by 14 publications

(10 citation statements)

References 9 publications

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“…[32][33][34][35][36] Thus, we hypothesized that ROS generated by either S100A9 or somatic gene mutations (SGMs) would direct activation of b-catenin in MDSs. In accordance with this, the mean percentage of ROS positive cells was increased 16.5-fold in MDS BM-MNCs (n 5 5) compared with normal donors (n 5 2) (P 5 .011) ( Figure 6A), with corresponding significant increases in ROS MFI (P 5 .028) ( Figure 6B).…”

Section: S100a9 and Mds Sgms Trigger Pyroptosis And B-catenin Activatmentioning

confidence: 99%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

275

350

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Key Points• Key biological features of MDSs are explained by NLRP3 inflammasome activation, which drives pyroptotic cell death and b-catenin activation.• Alarmin signals and founder gene mutations license this redox-sensitive inflammasome platform.Despite genetic heterogeneity, myelodysplastic syndromes (MDSs) share features of cytological dysplasia and ineffective hematopoiesis. We report that a hallmark of MDSs is activation of the NLRP3 inflammasome, which drives clonal expansion and pyroptotic cell death. Independent of genotype, MDS hematopoietic stem and progenitor cells (HSPCs) overexpress inflammasome proteins and manifest activated NLRP3 complexes that direct activation of caspase-1, generation of interleukin-1b (IL-1b) and IL-18, and pyroptotic cell death. Mechanistically, pyroptosis is triggered by the alarmin S100A9 that is found in excess in MDS HSPCs and bone marrow plasma. Further, like somatic gene mutations, S100A9-induced signaling activates NADPH oxidase (NOX), increasing levels of reactive oxygen species (ROS) that initiate cation influx, cell swelling, and b-catenin activation. Notably, knockdown of NLRP3 or caspase-1, neutralization of S100A9, and pharmacologic inhibition of NLRP3 or NOX suppress pyroptosis, ROS generation, and nuclear b-catenin in MDSs and are sufficient to restore effective hematopoiesis. Thus, alarmins and founder gene mutations in MDSs license a common redox-sensitive inflammasome circuit, which suggests new avenues for therapeutic intervention. (Blood. 2016;128(25):2960-2975

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Section: S100a9 and Mds Sgms Trigger Pyroptosis And B-catenin Activatmentioning

confidence: 99%

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Basiorka¹,

McGraw²,

Eksioglu³

et al. 2016

Blood

275

350

View full text Add to dashboard Cite

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“…Genes implicated in epigenetic control, including ASXL1 [8], TET2 [9], EZH2 [10], and DNMT3A [11], are frequently mutated in MDS patients, and DNA methylation at single genes [11, 12] or combinations of multiple genes [13] has been correlated with outcome. Gene silencing by hypermethylation at promoters of tumor‐associated genes or molecules involved in signaling may be important in the pathogenesis of MDS [14], and whole‐genome studies of DNA methylation are beginning to reveal the complexity of the disease at the epigenetic level [7, 15, 16]. We performed a genomewide methylation analysis of purified bone marrow CD34+ blast cells taken from MDS patients undergoing AZA treatment.…”

Section: Introductionmentioning

confidence: 99%

Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

Wong

Micklem

Taguchi

et al. 2014

Stem Cells Translational Medicine

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Myelodysplastic syndrome (MDS) is a disorder of hematopoietic stem cells (HSCs) that is often treated with DNA methyltransferase 1 (DNMT1) inhibitors (5-azacytidine [AZA], 5-aza-29-deoxycytidine), suggesting a role for DNA methylation in disease progression. How DNMT inhibition retards disease progression and how DNA methylation contributes to MDS remain unclear. We analyzed global DNA methylation in purified CD34+ hematopoietic progenitors from MDS patients undergoing multiple rounds of AZA treatment. Differential methylation between MDS phenotypes was observed primarily at developmental regulators not expressed within the hematopoietic compartment and was distinct from that observed between healthy hematopoietic cell types. After AZA treatment, we observed only limited DNA demethylation at sites that varied between patients. This suggests that a subset of the stem cell population is resistant to AZA and provides a basis for disease relapse. Using gene expression data from patient samples and an in vitro AZA treatment study, we identified differentially methylated genes that can be activated following treatment and that remain silent in the CD34+ stem cell compartment of high-risk MDS patients. Haploinsufficiency in mice of one of these genes (NR4A2) has been shown to lead to excessive HSC proliferation, and our data suggest that suppression of NR4A2 by DNA methylation may be involved in MDS progression. STEM CELLS TRANSLATIONAL

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“…S6C and S6D), indicating a potential negative correlation between Notch and Wnt signaling activity in T-ALL (30,31). Previously, the abnormal epigenetic modification of various critical Wnt signaling regulators was shown to be responsible for the aberrant activation of Wnt signaling in cancer cells (28,32). Therefore, we further validated the microarray data by examining the expression of 9 typical Wnt signaling regulators using qPCR (Fig.…”

Section: Mbd2 Ablation Impedes the Progression Of Notch1-driven T-allmentioning

confidence: 63%

MBD2 Ablation Impairs Lymphopoiesis and Impedes Progression and Maintenance of T-ALL

Zhou

Cheng

et al. 2018

Cancer Research

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Aberrant DNA methylation patterns in leukemia might be exploited for therapeutic targeting. In this study, we employed a genetically deficient mouse model to explore the role of the methylated DNA binding protein MBD2 in normal and malignant hematopoiesis. MBD2 ablation led to diminished lymphocytes. Functional defects of the lymphoid compartment were also observed after reconstitution of MBD2-deficient hematopoietic stem cells (HSC). In an established model of Notch1-driven T-cell acute lymphoblastic leukemia (T-ALL), MBD2 ablation impeded malignant progression and maintenance by attenuating the Wnt signaling pathway. In clinical specimens of human T-ALL, Wnt signaling pathway signatures were significantly enhanced and positively correlated with the expression and function of MBD2. Furthermore, a number of typical Wnt signaling inhibitory genes were abnormally hypermethylated in primary human T-ALL. Abnormal activation of Wnt signaling in T-ALL was switched off by MBD2 deletion, partially by reactivating epigenetically silenced Wnt signaling inhibitors. Taken together, our results define essential roles for MBD2 in lymphopoiesis and T-ALL and suggest MBD2 as a candidate therapeutic target in T-ALL. This study highlights a methylated DNA binding protein as a candidate therapeutic target to improve the treatment of T-cell acute lymphoblastic leukemias, as a new starting point for developing epigenetic therapy in this and other lymphoid malignancies. .

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Hypermethylation of Wnt antagonist gene promoters and activation of Wnt pathway in myelodysplastic marrow cells

Cited by 14 publications

References 9 publications

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype

Longitudinal Analysis of DNA Methylation in CD34+ Hematopoietic Progenitors in Myelodysplastic Syndrome

MBD2 Ablation Impairs Lymphopoiesis and Impedes Progression and Maintenance of T-ALL

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