Canonical WNT Signaling Pathway is Altered in Mesenchymal Stromal Cells From Acute Myeloid Leukemia Patients And Is Implicated in BMP4 Down-Regulation

Azevedo, Pedro; Corrêa, Stephany; Castelo-Branco, Morgana T.; Abdelhay, Eliana; Binato, Renata

doi:10.1016/j.tranon.2019.01.003

Cited by 9 publications

(8 citation statements)

References 53 publications

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“…Researches have revealed that APP as a novel clue was involved in leukemia cell proliferation, extramedullary infiltration, and prognosis in AML [ 36 , 37 ]. Azevedo et al observed that changes in BMP4 expression regulated by the WNT canonical signaling pathway may be a potential mechanism of leukemogenesis [ 38 ]. Binato et al also found that the decreasing expression of BMP4 in AML patients was related to the leukemogenic process [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Identifies Key Genes and Pathways in Acute Myeloid Leukemia Associated with DNMT3A Mutation

Chen

et al. 2020

BioMed Research International

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Background. DNA methyltransferase 3 alpha (DNMT3A) mutation was one of the most frequent genetic alterations in acute myeloid leukemia (AML), which was associated with poor prognosis and appeared to be a potential biomarker. Herein, we aimed to identify the key genes and pathways involved in adult AML with DNMT3A mutations and to find possible therapeutic targets for improving treatment. Methods. The RNA sequencing datasets of 170 adult AML patients were obtained from The Cancer Genome Atlas (TCGA) database. EdgeR of the R platform was used to identify the differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape and DAVID. And protein-protein interaction (PPI) network and clustering modules were analyzed with the STRING database and Cytoscape software. Results. Mutated DNMT3A resulted in a shorter overall survival (OS) in AML patients and obviously associated with age, blast percentage in peripheral blood, and FLT3 mutation. A total of 283 DEGs were detected, of which 95 were upregulated and 188 were downregulated. GO term analysis showed that DEGs were significantly enriched in neutrophil degranulation, myeloid cell differentiation, stem cell proliferation, positive regulation of neurological system process, leukocyte migration, and tissue morphogenesis. KEGG pathway enrichment analysis indicated that the pathway of cancer, PI3K-Akt signaling pathway, and transcriptional misregulation in cancer may play a crucial role in DNMT3A mutation AML. Seven hub genes (BMP4, MPO, THBS1, APP, ELANE, HOXA7, and VWF) had a significant prognostic value. Conclusion. Bioinformatics analysis in the present study provided novel targets for early diagnosis and new strategies for treatment for AML with DNMT3A mutation.

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Section: Discussionmentioning

confidence: 99%

Bioinformatics Analysis Identifies Key Genes and Pathways in Acute Myeloid Leukemia Associated with DNMT3A Mutation

Chen

et al. 2020

BioMed Research International

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“…Accumulating studies have shown that the strength of Wnt signaling should be fined-tuned for optimal function of HSCs 43 , 44 , and its dysregulation has been implicated in various types of leukemic cell development and resistance to therapy 44 , 64 – 66 . Similarly, dysregulated Wnt signals were observed in the BM stromal cells of leukemia patients 67 , 68 , whereas lack of canonical Wnt signaling in BM stroma led to deficiency of HSC repopulating activities 69 – 71 . Furthermore, altered signaling intensity of Wnt was shown to be associated with aging of the BM niche and hematopoietic cells 72 – 74 .…”

Section: Discussionmentioning

confidence: 93%

Ryk modulates the niche activity of mesenchymal stromal cells by fine-tuning canonical Wnt signaling

et al. 2020

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The importance of modulating the intensity of Wnt signaling has been highlighted in various biological models, but their mechanisms remain unclear. In this study, we found that Ryk—an atypical Wnt receptor with a pseudokinase domain—has a Wnt-modulating effect in bone marrow stromal cells to control hematopoiesis-supporting activities. We first found that Ryk is predominantly expressed in the mesenchymal stromal cells (MSCs) of the bone marrow (BM) compared with hematopoietic cells. Downregulation of Ryk in MSCs decreased their clonogenic activity and ability to support self-renewing expansion of primitive hematopoietic progenitors (HPCs) in response to canonical Wnt ligands. In contrast, under high concentrations of Wnt, Ryk exerted suppressive effects on the transactivation of target genes and HPC-supporting effects in MSCs, thus fine-tuning the signaling intensity of Wnt in BM stromal cells. This ability of Ryk to modulate the HPC-supporting niche activity of MSCs was abrogated by induction of deletion mutants of Ryk lacking the intracellular domain or extracellular domain, indicating that the pseudokinase-containing intracellular domain mediates the Wnt-modulating effects in response to extracellular Wnt ligands. These findings indicate that the ability of the BM microenvironment to respond to extracellular signals and support hematopoiesis may be fine-tuned by Ryk via modulation of Wnt signaling intensity to coordinate hematopoietic activity.

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“…Mbalaviele and colleagues demonstrated that a constitutive active b-catenin mutant synergized with BMP-2 to induce in vitro mineralization of osteoblast cell lines and in vivo calvarial bone formation (32). Similarly, Azevedo et al reported that the decrease in BMP4 expression in hMSCs from patients with acute myeloid leukemia was associated with the decrease in b-catenin (33). Yet, cWnt signaling has also been established to inhibit BMP4 expression as shown in Xenopus development and murine corneal epithelium (34,35).…”

Section: Discussionmentioning

confidence: 98%

β-Catenin Limits Osteogenesis on Regenerative Materials in a Stiffness-Dependent Manner

Zhou

Ren

Oberoi

et al. 2021

Preprint

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Targeted refinement of regenerative materials requires mechanistic understanding of cell-material interactions. The nanoparticulate mineralized collagen glycosaminoglycan (MC-GAG) scaffold is a porous biomaterial that promotes regenerative healing of calvaria defects in vivo without addition of exogenous growth factors or progenitor cells, suggesting its potential as an off-the-shelf implant for reconstructing skull defects. In this work, we evaluate the relationship between material stiffness, a tunable MC-GAG property, and activation of the canonical Wnt (cWnt) signaling pathway. Primary human bone marrow-derived mesenchymal stem cells (hMSCs) were differentiated on two MC-GAG scaffolds varying by stiffness (non-crosslinked, NX-MC, 0.3 kPa vs. conventionally crosslinked, MC, 3.9 kPa). hMSCs exhibited increased expression of activated β-catenin, the major cWnt intracellular mediator, and the mechanosensitive YAP protein with near complete subcellular colocalization in stiffer MC scaffolds. Small molecule Wnt pathway inhibitors reduced activated β-catenin and YAP protein quantities and colocalization, osteogenic differentiation, and mineralization on MC, with no effects on NX-MC. Concomitantly, Wnt inhibitors increased BMP4 and phosphorylated Smad1/5 (p-Smad1/5) expression on MC, but not NX-MC. Unlike non-specific Wnt pathway downregulation, isolated canonical Wnt inhibition with β-catenin knockdown increased osteogenic gene expression and mineralization specifically on the stiffer MC. β-catenin knockdown also increased p-Smad1/5, Runx2, and BMP4 expression only on the stiffer MC material. Our data indicates stiffness-induced activation of the Wnt and mechanotransduction pathways promotes osteogenesis in MC-GAG scaffolds. However, activated β-catenin is a limiting agent and may serve as a useful target or readout for optimal modulation of stiffness in skeletal regenerative materials.

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Canonical WNT Signaling Pathway is Altered in Mesenchymal Stromal Cells From Acute Myeloid Leukemia Patients And Is Implicated in BMP4 Down-Regulation

Cited by 9 publications

References 53 publications

Bioinformatics Analysis Identifies Key Genes and Pathways in Acute Myeloid Leukemia Associated with DNMT3A Mutation

Bioinformatics Analysis Identifies Key Genes and Pathways in Acute Myeloid Leukemia Associated with DNMT3A Mutation

Ryk modulates the niche activity of mesenchymal stromal cells by fine-tuning canonical Wnt signaling

β-Catenin Limits Osteogenesis on Regenerative Materials in a Stiffness-Dependent Manner

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