Wnt signaling somatic alterations in apc-associated fap adenomas

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22046-e22046
Author(s):  
A. Obrador-Hevia ◽  
F. Chin ◽  
S. Gonzalez ◽  
F. Vilardell ◽  
D. Cordero ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Genetic Material ◽  
Point Mutations ◽  
Normal Mucosa ◽  
Median Number ◽  
Nuclear Accumulation ◽  
Mrna Levels ◽  
Dna And Rna ◽  
Apc Mutations

e22046 Background: APC mutations are believed to constitutively activate the wnt pathway in colorectal tumors. Our goal was to comprehensively characterize Wnt signaling components in a set of APC-associated FAP tumors both at the DNA and RNA levels. Methods: Sixty adenomas from FAP cases harboring pathogenic APC mutations were included (10 adenomas and 1 normal mucosa per case). Somatic APC and KRAS alterations, β-catenin immunostaining and qRT-PCR of APC, MYC, AXIN2 and SFRP1 were analyzed. aCGH was also assessed in 26 FAP adenomas and 24 additional paired normal-adenoma-carcinoma samples. Results: A second APC alteration was present in 30 (50%) of adenomas (26 LOH and 4 point mutations). LOH was only occasionally associated with loss of genetic material. In 3 of 6 cases APC mRNA was overexpressed in macroscopically normal mucosa. In these cases diminished APC levels mRNA were observed in 11 of 30 adenomas analyzed.. In the remaining 3 cases APC mRNA was already underexpressed in normal mucosa with only 3 of 30 adenomas showing further underexpression. In FAP normal mucosae MYC was overexpressed (logratio range: 3.37–5.66). All adenomas showed further MYC (logratio range: 1.78–2.92) and AXIN2 overexpression (logratio range: 1.62–4.65), corregulating with APC mRNA levels (r=0.31 for MYC; r=0.59 for AXIN2). β-catenin nuclear immunostaining was detected in 80% of adenomas correlating with MYC mRNA levels. SFRP1 was underexpressed in all tumors (logratio range= -3.06–27). While copy number changes were rare in adenomas (median number :2.5; range 0–5). DNA changes were more often detected in areas containing wnt genes when FAP and sporadic tumors were jointly analyzed (p=0.02). Conclusions: Wnt pathway is altered, at the DNA and/or RNA level, in all APC mutant FAP tumors. MYC overexpression is a universal event that correlates with APC and AXIN2 expression levels as well as bcatenin nuclear accumulation. No significant financial relationships to disclose.

Transcriptional Silencing of the Wnt-Antagonist Dickkopf-1 (DKK1) by Promoter Methylation Unleashes Aberrant Wnt Signaling In Advanced Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1919-1919
Author(s):  
Kinga A Kocemba ◽  
Richard W Groen ◽  
Harmen van Andel ◽  
Karene Mahtouk ◽  
Marie Jose Kersten ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Cell Lines ◽  
Wnt Pathway ◽  
Conflicts Of Interest ◽  
Cpg Island ◽  
Nuclear Accumulation ◽  
Aberrant Methylation ◽  
Dkk1 Expression ◽  
Osteolytic Bone Disease

Abstract Abstract 1919 Aberrant activation of the Wnt/β-catenin pathway is implicated in driving the formation of various human cancers. Recent studies indicate that the Wnt pathway plays at least two distinct roles in the pathogenesis of multiple myeloma (MM): i) Aberrant, presumably autocrine, activation of canonical Wnt signaling in MM cells promotes tumor proliferation and metastasis; ii) Overexpression of the Wnt inhibitor Dickkopf1 (DKK1), contributes to osteolytic bone disease by inhibiting osteoblast differentiation. Since DKK1 itself is a target of TCF/β-catenin mediated transcription, these findings suggests the presence of a negative feedback loop in MM, in which DKK1 acts as a potential tumor suppressor. In line with this hypothesis, we show here that DKK1 expression is lost in most MM cell lines and in a subset of patients with advanced MM. This loss is correlated with activation of the Wnt pathway, as demonstrated by increased nuclear accumulation of β-catenin. Analysis of the DKK1 promoter revealed CpG island methylation in several MM cell lines as well as in MM cells from patients with advanced MM. Moreover, demethylation of the DKK1 promoter restores DKK1 expression, which results in inhibition of β-catenin/TCF-mediated gene transcription in MM lines. Taken together, our data identify aberrant methylation of the DKK1 promoter as a cause of DKK1 silencing in advanced stage MM, which may play an important role in the progression of MM by unleashing Wnt signaling. Disclosures: No relevant conflicts of interest to declare.

OTT-MKL1 and MKL1 Inhibit Wnt Signaling.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2250-2250
Author(s):  
Stephanie Halene ◽  
Ee-chun Cheng ◽  
Vincent Schulz ◽  
David Tuck ◽  
Diane Krause
Keyword(s):  
Cell Death ◽  
Wnt Signaling ◽  
Transcriptional Activation ◽  
Wnt Pathway ◽  
Fusion Gene ◽  
Apoptotic Cell ◽  
Dominant Negative ◽  
Nuclear Accumulation ◽  
Transactivation Domain ◽  
Hel Cells

Abstract The OTT-MKL1 fusion gene product is generated as a result of t(1;22) in a subset of acute megakaryoblastic leukemia predominantly encountered in young children. Due to myelofibrosis and the age at presentation, patient samples are scarce. We generated Human Erythroid Leukemia (HEL) cell derived cell lines with tet-inducible OTT, MKL1 and OTT-MKL1 to further elucidate the function of the respective proteins. HEL cells can be induced to differentiate down the megakaryocyte lineage by TPA. Induction with doxycycline resulted in transcription and translation of the respective genes within hours. While overexpression of MKL1 led to enhancement of megakaryocytic differentiation, both OTT and OTT-MKL1 overexpression led to cell death over the course of several days by apoptosis as evident by staining for Annexin V and morphology. The apoptotic cell death was greatly enhanced by concomitant induction of differentiation by TPA. We performed microarray analysis comparing uninduced and 8-hour tet-induced samples in the presence or absence of TPA. While overexpression of OTT had only a minimal effect on the transcriptome of the HEL cells, both MKL1 and OTT-MKL1 significantly affected the gene expression of many genes. Using a false discovery rate cut-off of p < 0.05, and assessing only those genes whose expression changed by greater than 2-fold, OTT-MKL1 and MKL1 induced the upregulation of 157 and 168 genes, respectively, and the downregulation of 56 and 62 genes, respectively. Only 20 genes were upregulated by both OTT-MKL1 and MKL1, and 12 genes were downregulated greater than 2-fold by both OTT-MKL1 and MKL1. GeneGo analysis comparing OTT-MKL1 over-expressing versus non-expressing cells revealed over-representation of the Wnt pathway. Among the differentially expressed genes implicated in the Wnt pathway were Frat1 and Frat2, which have been shown to inhibit GSK3β and lead to β-catenin nuclear accumulation, and thus stimulation of the Wnt pathway. At the same time, inhibitory NLK was upregulated and several down-stream targets of the Wnt pathway were downregulated. Spenito, the homolog of OTT in Drosophila, is known to have promoter-specific activating and inhibiting effects on Wnt target genes. We thus performed reporter assays to study the effects of OTT, MKL1 and OTT-MKL1 on the Wnt pathway. Using the TOP-/FOP-FLASH reporter system in 293T cells, there was a dose-dependent inhibition of β-catenin-mediated activation of the Tcf/Lef binding site promoter by MKL1 and OTT-MKL1. Full length OTT showed a minimal stimulatory effect only at low doses., while N-terminal OTT, lacking the SPOC domain and a dominant negative form of MKL1 lacking the transactivation domain each enhanced β-catenin induced Tcf/Lef mediated transcriptional activation. Studies to define the domains of OTT and MKL1 and the underlying mechanisms in hematopoietic cells are underway. These results suggest that MKL1 and OTT-MKL1 inhibit canonical Wnt signaling by inhibiting β-catenin induced transcription.

Involvement of T-Cells in the Bone Pathology of Multiple Myeloma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5340-5340
Author(s):  
Emmanouel Simantirakis ◽  
Nikolaos Giannakoulas ◽  
Elena Siapati ◽  
George Vassilopoulos
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Conflicts Of Interest ◽  
Laboratory Data ◽  
Receptor Expression ◽  
Mrna Levels ◽  
Bone Pathology ◽  
Hematopoietic Stem

Abstract Introduction: Multiple myeloma (MM) is a plasma cell dyscrasia that is heavily dependent on a permissive BM micro-environment. Components of the WNT pathway have been implicated in this process and specifically, WNT-inhibitors such as Dkk1, have been blamed for the osteolytic lesions of MM. WNT signaling is required for proper osteoblast development while the pathway is also involved in enhancing the self renewal potential of various stem cells. A source of WNT ligands in the BM are the T-cells; when stimulated by parathormone, T-cells secrete wnt10b that affects hematopoietic stem cell numbers. In the present study, we evaluated WNT signaling in the T-cells of patients with MM in order to test whether these bystander T-cells have an altered phenotype that could influence disease pathology. Methods: A total of 18 MM patients was analyzed after informed consent was obtained; the patients underwent BM biopsy for diagnostic and staging purposes. T-cells were isolated from BM mononuclear cells using magnetic beads with a purity of around 90%. Normal controls were T-cells isolated from healthy subjects. RNA was isolated and analyzed by RT-PCR for expression of PTH receptor (PTH1R), wnt10b and the canonical WNT signal transducer, b-catenin (bCAT). Results and discussion: BM concentration of T-cells was 15%, close to the normal values, indicating no major deviation from normal conditions. Activity of the WNT pathway was estimated by bCAT mRNA levels; relative to the control, bCAT levels in MM T-cells were uniformily suppressed. In a total of 8 evaluable samples, there was a 3x decrease in bCAT levels. Although WNT activity could be influenced by different factors, there is a possibility that it may be related to PTH activity and PTH receptor expression on patient T-cells. In all our cases, calcium was recorded within normal range and PTH values were also normal. However, PTH1R mRNA levels in MM T-cells were 14.2x lower compared to normal T-cells, a value that argues for a biological role in disease pathogenesis. A direct consequence of low PTH1R mRNA levels, according to our hypothesis, would lead to a decrease in WNT10b. Indeed, WNT10b levels were on average 90% of the normal with relative wide variation; in 3 samples, there was an average 3.2x increase while in 8, the levels were on average 21% of normal. On the clinical level, lower wnt10b activity, was more often associated with bone pathology while higher wnt10b activity was more often associated with extramedullary plasmacytomas. Our data show that T-cells may not be bystanders in the MM disease progression and certain manifestations sush as bone disease, could be associated with, aberrant T cell function. Ongoing studies are under way to link clinical and laboratory data. Disclosures No relevant conflicts of interest to declare.

scholarly journals Inhibition of Canonical WNT Signaling in the Bone Marrow Niche Prevents the Development of Disease in a Mouse MDS Model with Apc Haploinsufficiency

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1129-1129
Author(s):  
Angela Stoddart ◽  
Jianghong Wang ◽  
Chunmei Hu ◽  
Anthony A. Fernald ◽  
Elizabeth M. Davis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Wnt Signaling ◽  
Median Survival ◽  
Wnt Pathway ◽  
Negative Regulator ◽  
Nuclear Accumulation ◽  
Bone Marrow Niche ◽  
Canonical Wnt Signaling ◽  
Casein Kinase 1 ◽  
Canonical Wnt

Abstract The myelodysplastic syndromes (MDS) include a spectrum of clonal hematopoietic stem cell (HSC) disorders that are characterized by ineffective hematopoiesis, peripheral cytopenia(s), morphologic dysplasia, and a variable propensity to transform to acute myeloid leukemia (AML). A del(5q) is the most common recurring cytogenetic abnormality in MDS, and is observed in 10-20% of primary MDS, and 40% of therapy-related MDS and AML. Our lab has had a long-standing interest in understanding how loss of function of tumor suppressor genes on 5q, such as APC, contributes to the pathogenesis of MDS and AML. Apc is a key negative regulator of the canonical β-catenin (Ctnnb1)/WNT signaling pathway.WNT signaling has been implicated in self-renewal of HSCs and the regulation of hematopoiesis, and the deregulation of WNT signaling is associated with the development of hematological malignancies. Recent data suggests that WNT activation in the bone marrow (BM) microenvironment or niche may also contribute to the development of AML. Kode et al. (Nature 506:240, 2014) showed that expression of activated β-catenin in osteoblast cells in the BM microenvironment leads to AML in mice. Thus, aberrant WNT signaling in HSCs and/or the microenvironment that supports them may contribute to malignant transformation. We previously used a conditional mouse model (Mx1-Cre+, Apc fl/+, referred to as Apcdel/+) and showed that haploinsufficiency of Apc leads to ineffective hematopoiesis (Blood 115:3481, 2010). Interestingly, haploinsufficient loss of Apc in the niche stromal cells, but not the hematopoietic progenitors, led to the development of MDS, characterized by a severe macrocytic anemia, dyserythropoiesis, megakaryocytic proliferation, and mild granulocytic dysplasia (Blood 123:228, 2014). In this study, we sought to determine whether haploinsufficient loss of Apc, mediates this disease through modulating WNT signaling, versus other Apc functions, and whether inhibition of WNT signaling could prevent the development of MDS in Apcdel/+mice. Here, we demonstrate thatsignaling through the canonical WNT pathway mediates the development of MDS in Apc haploinsufficient mice. Specifically, loss of one copy of Ctnnb1 is sufficient to prevent the development of MDS in Apcdel/+ mice. Compared to the median survival of Apc del/+ mice, which was 255 days, all Apc del/+, Ctnnb1 del/+ mice survived until the end of the study (~400 days) (P<0.001). In addition, we showed that altered canonical WNT signaling in the BM microenvironment is responsible for the disease. Using bone marrow transplantation of wild type BM cells, we showed that Apc del/+ recipients develop MDS and die of a fatal anemia by ~4 months of age. In contrast, Apc del/+, Ctnnb1 del/+ recipients survived on average 8-10 months longer (median survival 115 vs 413 days, P <0.0001). To determine if we could prevent the development of MDS, we treated mice with the FDA-approved antihelminth drug, Pyrvinium, an inhibitor of the WNT pathway via activation of casein kinase 1 alpha and β-catenin degradation. Apc del/+mice in the control DMSO-treated group developed disease with a median survival of 227 days; however, during this time period, none of the Pyrvinium-treated mice became moribund. The mice succumbed to MDS about 100 days after Pyrvinium treatment was suspended, indicating that the drug prevented the development of disease, and must be continuously administered. We also showed that Pyrvinium treatment does not have to be administered before anemia develops; however, the drug is more effective when it is started in animals that display mild-to-moderate anemia rather than severe anemia. These studies have important implications for the treatment of certain forms of MDS. Kode et al. (Nature 506:240, 2014) showed nuclear accumulation of β-catenin in osteoblasts from ~40% of MDS/AML patients, supporting the idea that activated WNT signaling in the BM microenvironment may contribute to the development of disease. Targeting the tumor microenvironment is now recognized as a promising approach to complement current therapies, and our data highlight a potential new strategy of targeting the WNT signaling pathway for treating some forms of MDS. Disclosures No relevant conflicts of interest to declare.

DDRE-15. Sema3C SIGNALING CONFERS RESISTANCE TO Wnt INHIBITION IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi77-vi77
Author(s):  
Jing Hao ◽  
Xiangzi Han ◽  
Haidong Huang ◽  
xingjiang yu ◽  
Shideng Bao ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Wnt Pathway ◽  
Nuclear Accumulation ◽  
Tumor Control ◽  
Cell Fractionation ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt ◽  
Wnt Inhibitors

Abstract BACKGROUND Wnt signaling is widely dysregulated in cancer. The therapeutic potential of Wnt inhibitors appears promising in preclinical studies. However, they have uniformly failed clinical trials. How cancer cells develop Wnt inhibitor resistance is poorly understood. Current Wnt inhibitors are designed targeting either ligand or receptor. We hypothesized cancer cells will bypass ligand-receptor interaction through an unknown mechanism. We focused on the neurodevelopmental signaling program of Semaphorin 3C (Sema3C) that is upregulated in 85% of GBM and regulates glioma stem-cell-driven tumor progression. RESULTS Porcupine inhibitor LGK974 reduced TCF1 expression in the GBM tumor mouse models, suggesting successful target engagement in vivo. However, it failed to prolong the overall survival. Sema3C expression strongly correlated with TCF1 expression in human GBM samples by immunohistochemical analysis. Genetic inhibition of Sema3C and TCF1 together prolonged animal survival more than either alone, indicating better control of Wnt pathway signaling with dual pathway blockade. Immunofluorescence and cell fractionation studies revealed that Sema3C signaling drove β-catenin nuclear accumulation. Sema3C regulates transactivation of Wnt target genes including TCF1, c-Myc and c-Met. Sema3C pathway activates Rac1. It is reported that Rac1 activates β-catenin and promotes β-catenin nuclear accumulation. In GSCs, constitutively active Rac1 restored β-catenin nuclear localization and rescued TCF1 and c-Myc down-regulation in the setting of Sema3C silencing. Sema3C can drive canonical Wnt signaling even when Wnt ligand secretion is blocked. Together, the data support that GSCs can escape Wnt inhibition through Sema3C and Rac1. CONCLUSIONS Sema3C signaling drives canonical Wnt signaling, providing an escape mechanism for cancer cells despite Wnt ligand-receptor interruption. Sema3C-β-catenin signaling promotes GSC self-renewal and tumor progression. Upstream Wnt pathway inhibition alone is insufficient to control tumors. Our data provide a therapeutic strategy of dual blockade of Wnt and Sema3C pathways to provide clinically significant tumor control.

scholarly journals The EDD E3 ubiquitin ligase ubiquitinates and up-regulates β-catenin

2011 ◽  
Vol 22 (3) ◽  
pp. 399-411 ◽  
Author(s):  
Avital Hay-Koren ◽  
Michal Caspi ◽  
Alona Zilberberg ◽  
Rina Rosin-Arbesfeld
Keyword(s):  
Wnt Signaling ◽  
Ubiquitin Ligase ◽  
Wnt Pathway ◽  
Glycogen Synthase ◽  
Wnt Signaling Pathway ◽  
E3 Ubiquitin Ligase ◽  
Nuclear Accumulation ◽  
Protein Levels ◽  
Ubiquitin System ◽  
Gsk 3Β

Wnt/β-catenin signaling plays a central role in development and is also involved in a diverse array of diseases. β-Catenin activity is tightly regulated via a multiprotein complex that includes the kinase glycogen synthase kinase-3β (GSK-3β). GSK-3β phosphorylates β-catenin, marking it for ubiquitination and degradation via the proteasome. Thus in regulation of the Wnt pathway, the ubiquitin system is known to be involved mostly in mediating the turnover of β-catenin, resulting in reduced Wnt signaling levels. Here we report that an arm of the ubiquitin system increases β-catenin protein levels. We show that GSK-3β directly interacts with the E3 ubiquitin ligase identified by differential display (EDD) that also binds β-catenin. Expression of EDD leads to enhanced nuclear accumulation of both GSK-3β and β-catenin and results in up-regulation of β-catenin expression levels and activity. Importantly, EDD ubiquitinates β-catenin through Lys29- or Lys11-linked ubiquitin chains, leading to enhanced stability of β-catenin. Our results demonstrate a role for the ubiquitin system in up-regulation of the Wnt signaling pathway, suggesting that EDD could function as a colorectal oncogene.

scholarly journals Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3446
Author(s):  
Stefan Koch
Keyword(s):  
Transcription Factors ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Treatment Options ◽  
Wnt Signaling Pathway ◽  
Tissue Homeostasis ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Signaling Activity

Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

HCl-induced inflammatory mediators in cat esophageal mucosa and inflammatory mediators in esophageal circular muscle in an in vitro model of esophagitis

2006 ◽  
Vol 290 (6) ◽  
pp. G1307-G1317 ◽  
Author(s):  
Ling Cheng ◽  
Weibiao Cao ◽  
Claudio Fiocchi ◽  
Jose Behar ◽  
Piero Biancani ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Platelet Activating Factor ◽  
Circular Muscle ◽  
Muscle Layer ◽  
Normal Mucosa ◽  
Esophageal Mucosa ◽  
Mrna Levels ◽  
Physiol Gastrointest Liver ◽  
Krebs Buffer

Platelet-activating factor (PAF) and interleukin-6 (IL-6) are produced in the esophagus in response to HCl and affect ACh release, causing changes in esophageal motor function similar to esophagitis (Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, and Harnett KM. Am J Physiol Gastrointest Liver Physiol 289: G418–G428, 2005). We therefore examined HCl-activated mechanisms for production of PAF and IL-6 in cat esophageal mucosa and circular muscle. A segment of normal mucosa was tied at both ends, forming a mucosal sac (Cheng L, Cao W, Fiocchi C, Behar J, Biancani P, and Harnett KM. Am J Physiol Gastrointest Liver Physiol 289: G860–G869, 2005) that was filled with acidic Krebs buffer (pH 5.8) or normal Krebs buffer (pH 7.0) as control and kept in oxygenated Krebs buffer for 3 h. The supernatant of the acidic sac (MS-HCl) abolished contraction of normal muscle strips in response to electric field stimulation. The inhibition was reversed by the PAF antagonist CV3988 and by IL-6 antibodies. PAF and IL-6 levels in MS-HCl and mucosa were significantly elevated over control. IL-6 levels in mucosa and supernatant were reduced by CV3988, suggesting that formation of IL-6 depends on PAF. PAF-receptor mRNA levels were not detected by RT-PCR in normal mucosa, but were significantly elevated after exposure to HCl, indicating that HCl causes production of PAF and expression of PAF receptors in esophageal mucosa and that PAF causes production of IL-6. PAF and IL-6, produced in the mucosa, are released to affect the circular muscle layer. In the circular muscle, PAF causes production of additional IL-6 that activates NADPH oxidase to induce production of H2O2. H2O2 causes formation of IL-1β that may induce production of PAF in the muscle, possibly closing a self-sustaining cycle of production of inflammatory mediators.

Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease

Blood ◽  
2021 ◽  
Author(s):  
Yun Zhang ◽  
Lichong Shen ◽  
Katja Dreissigacker ◽  
Honglin Zhu ◽  
Thuong Trinh-Minh ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Graft Versus Host Disease ◽  
Molecular Mechanisms ◽  
Nuclear Accumulation ◽  
Clinical Use ◽  
Canonical Wnt Signaling ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Canonical Wnt

Chronic graft-versus-host disease (cGvHD) is a major life-threatening complication of allogeneic hematopoietic stem cell transplantation. The molecular mechanisms underlying cGvHD remain poorly understood and targeted therapies are not well established for clinical use. Here, we examined the role of the canonical WNT pathway in sclerodermatous cGvHD (sclGvHD). WNT signaling was activated in human sclGvHD with increased nuclear accumulation of the transcription factor β-catenin and WNT-biased gene expression signature in lesional skin. Treatment with highly selective tankryase inhibitor G007-LK, CK1α agonist pyrvinium or LRP6 inhibitor salinomycin, abrogated the activation of WNT signaling and protected against experimental cGvHD, without significant impact on graft-versus-leukemia effect (GvL). Treatment with G007-LK, pyrvinium or salinomycin almost completely prevented the development of clinical and histological features in the B10.D2 (H-2d)→BALB/c (H-2d) and in the LP/J (H-2b)→C57BL/6 (H-2b) model of sclGvHD. Inhibition of canonical WNT signaling reduced the release of extracellular matrix from fibroblasts and reduced leukocyte influx, suggesting that WNT signaling stimulates fibrotic tissue remodeling by direct effects on fibroblasts and by indirect, inflammation-dependent effects in sclGvHD. Our findings may have direct translational potential, as pyrvinium is in clinical use and tankyrase inhibitors are in clinical trials for other implications.

scholarly journals Integrative Genomics with Mediation Analysis in a Survival Context

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Szilárd Nemes ◽  
Toshima Z. Parris ◽  
Anna Danielsson ◽  
Zakaria Einbeigi ◽  
Gunnar Steineck ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Genomic Analysis ◽  
Mrna Levels ◽  
Integrative Genomics ◽  
Asymptotic Results ◽  
Data Set ◽  
Cancer Data ◽  
Dna And Rna ◽  
Altered Gene

DNA copy number aberrations (DCNA) and subsequent altered gene expression profiles may have a major impact on tumor initiation, on development, and eventually on recurrence and cancer-specific mortality. However, most methods employed in integrative genomic analysis of the two biological levels, DNA and RNA, do not consider survival time. In the present note, we propose the adoption of a survival analysis-based framework for the integrative analysis of DCNA and mRNA levels to reveal their implication on patient clinical outcome with the prerequisite that the effect of DCNA on survival is mediated by mRNA levels. The specific aim of the paper is to offer a feasible framework to test the DCNA-mRNA-survival pathway. We provide statistical inference algorithms for mediation based on asymptotic results. Furthermore, we illustrate the applicability of the method in an integrative genomic analysis setting by using a breast cancer data set consisting of 141 invasive breast tumors. In addition, we provide implementation in R.

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