β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)

Li, Liping; Sheng, Yue; Li, Wenshu; Hu, Chao; Mittal, Nupur; Tohyama, Kaoru; Seba, A.; Zhao, You Yang; Ozer, Howard; Zhu, Tongyu; Qian, Zhijian

doi:10.1158/0008-5472.can-17-0202

Cited by 20 publications

(19 citation statements)

References 47 publications

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“…Previous studies have reported that the Wnt/β-catenin pathway is related to cell development and proliferation [23][24][25]. Therefore, the present study considered the Wnt/β-catenin pathway as a target pathway for aspirin-induced apoptosis.…”

Section: Aspirin Inhibited the Canonical Wnt/β-catenin Pathway Of Tscmentioning

confidence: 99%

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

Wang

Tang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used in clinical practice to relieve fever and pain. Aspirin, as a representative NSAID, has been widely used in the treatment of tendinopathy. Some reports have demonstrated that aspirin can induce apoptosis in cancer cells. However, evidence regarding aspirin treatment for tendinopathy, especially the effect of this treatment on tendon stem cells (TSCs), is lacking. Understanding the effect of aspirin on tendinopathy may provide a basis for the rational use of NSAIDs in clinical practice. The aim of our study was to determine whether aspirin induces apoptosis in rat TSCs via the Wnt/β-catenin pathway. Methods: First, we used flow cytometry and fluorescence to detect TSC apoptosis. Protein expression of the apoptosis-related caspase-3 pathway was investigated via western blot analysis. Next, we used western blotting to determine the effect of aspirin on the Wnt/β-catenin pathway. We used immunostaining to detect the levels of Bcl2, cleaved caspase-3, and P-β-catenin in the Achilles tendon. Finally, we used flow cytometry, fluorescence, and western blotting to investigate the aspirin-induced apoptosis of TSCs via the Wnt/β-catenin pathway. Results: Aspirin induced morphological apoptosis in rat TSCs via the mitochondrial/caspase-3 pathway and induced cellular apoptosis in the Achilles tendon. Apoptosis was partly reversed after adding the Wnt signaling activator Wnt3a and lithium chloride (LiCl, a GSK-3β inhibitor). Aspirin administration led to a dose-dependent increase in COX-2 expression. Apoptosis was promoted after adding the COX-2 inhibitor NS398. Conclusion: The Wnt/β-catenin pathway plays a vital role in aspirin-induced apoptosis by regulating mitochondrial/caspase-3 function. Elevating COX-2 levels may protect cells against apoptosis. More importantly, the results remind us to consider the apoptotic effect of aspirin on TSCs and tendon cells when aspirin is administered to treat tendinopathy. The relationship between the positive and negative effects of aspirin remains a subject for future study.

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Section: Aspirin Inhibited the Canonical Wnt/β-catenin Pathway Of Tscmentioning

confidence: 99%

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

Wang

Tang

et al. 2018

Cell Physiol Biochem

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“…Graded Wnt signaling has differential effects such that high activation leads to BM failure, while at a lesser degree, HSC expansion occurs . In one study, genetic deletion of a single allele of β‐catenin rescued ineffective hematopoiesis in an Apc haploinsufficient mouse model with several characteristics of del(5q) MDS . Suppression of β‐catenin by indomethacin or shRNA also led to reduced proliferation and survival of human leukemia cells with del(5q) but not of control leukemia cell lines in vitro .…”

Section: Wnt/β‐catenin Signaling In Hsc Expansionmentioning

confidence: 72%

“…45 β-catenin inactivation also inhibited the progression to leukemia in xenograft mice reconstituted with del(5q) leukemia cell lines. 45 These data suggest that the Wnt/β-catenin pathway may be a key therapeutic target for del(5q) MDS.…”

Section: W Nt/β -C Atenin S I G Naling In H Sc E Xpans Ionmentioning

confidence: 95%

“…44 In one study, genetic deletion of a single allele of β-catenin rescued ineffective hematopoiesis in an Apc haploinsufficient mouse model with several characteristics of del(5q) MDS. 45 Suppression of β-catenin by indomethacin or shRNA also led to reduced proliferation and survival of human leukemia cells with del(5q) but not of control leukemia cell lines in vitro. 45 β-catenin inactivation also inhibited the progression to leukemia in xenograft mice reconstituted with del(5q) leukemia cell lines.…”

Section: W Nt/β -C Atenin S I G Naling In H Sc E Xpans Ionmentioning

confidence: 99%

“…45 Suppression of β-catenin by indomethacin or shRNA also led to reduced proliferation and survival of human leukemia cells with del(5q) but not of control leukemia cell lines in vitro. 45 β-catenin inactivation also inhibited the progression to leukemia in xenograft mice reconstituted with del(5q) leukemia cell lines. 45 These data suggest that the Wnt/β-catenin pathway may be a key therapeutic target for del(5q) MDS.…”

Section: W Nt/β -C Atenin S I G Naling In H Sc E Xpans Ionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular pathogenesis of myelodysplastic syndromes with deletion 5q

Lee

List

Sallman

2019

European J of Haematology

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The molecular pathogenesis of deletion 5q (del(5q)) myelodysplastic syndrome (MDS) has recently been realized as a result of major advances in our understanding of the mechanisms responsible for clinical phenotype. Identification of commonly deleted genes such as RPS14, miRNA‐145, HSPA9, CD78, and CSNK1a1 have elucidated the precise biological changes responsible for the anemia, leukopenia, and thrombocytosis that characterizes del(5q) MDS and highlighted the importance of allelic haploinsufficiency in the hematological phenotype. Recent elegant investigations have also identified a critical role of innate immune signaling in del(5q) pathogenesis. TP53 and Wnt/β‐catenin pathways have also been found to be involved in clonal expansion and progression of the disease as well as resistance and poor outcomes to available therapy. Understanding the molecular pathogenesis of the disease has provided a critical foundation in identifying the biological targets of lenalidomide in del(5q) MDS, which has led to the development of novel therapeutic agents in hematologic malignancies as well as potential alternative targets to exploit in patients who have failed lenalidomide treatment.

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Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q)

et al. 2021

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Myelodysplastic syndrome (MDS) with isolated deletion of chromosome 5q (MDS del5q) is a distinct subtype of MDS with quite favorable prognosis and excellent response to treatment with lenalidomide. Still, a relevant percentage of patients do not respond to lenalidomide and even experience progression to acute myeloid leukemia (AML). In this study, we aimed to investigate whether global DNA methylation patterns could predict response to lenalidomide. Genome-wide DNA methylation analysis using Illumina 450k methylation arrays was performed on n=51 patients with MDS del5q who were uniformly treated with lenalidomide in a prospective multicenter trial of the German MDS study group. To study potential direct effects of lenalidomide on DNA methylation, 17 paired samples pre- and post-treatment were analyzed. Our results revealed no relevant effect of lenalidomide on methylation status. Furthermore, methylation patterns prior to therapy could not predict lenalidomide response. However, methylation clustering identified a group of patients with a trend towards inferior overall survival. These patients showed hypermethylation of several interesting target genes, including genes of relevant signaling pathways, potentially indicating the evaluation of novel therapeutic targets.

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β-Catenin Is a Candidate Therapeutic Target for Myeloid Neoplasms with del(5q)

Cited by 20 publications

References 47 publications

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

High Concentration of Aspirin Induces Apoptosis in Rat Tendon Stem Cells via Inhibition of the Wnt/β-Catenin Pathway

Molecular pathogenesis of myelodysplastic syndromes with deletion 5q

Genome-wide DNA methylation analysis pre- and post-lenalidomide treatment in patients with myelodysplastic syndrome with isolated deletion (5q)

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