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Wnt Pathway Contributes to the Protection of Acute Lymphoblastic Leukemia Cells by Bone Marrow Stromal Cells and May Be a Therapeutic Target

ABSTRACT: Acute lymphoblastic leukemia (ALL) is the most common cancer in children and one of the most common cancers in adults. Although most children with ALL can be cured, approximately 60% of adults with ALL develop drug resistance or experience relapse and cannot be cured with traditional chemotherapy. One possible reason that treatment fails to eradicate ALL cells is that residual leukemia cells are protected by various components of the bone marrow microenvironment, such as marrow stromal cells (MSCs). To evaluate the effects of MSCs on ALL cell survival and response to chemotherapy, we co-cultured ALL cells with human or murine MSCs. We found that both human and murine MSCs protected human ALL cell lines and primary ALL cells from spontaneous and Ara-C-induced apoptosis. MSCs also modulated the cell cycle and increased ALL cell proliferation. Specifically, we found that Wnt signaling activation contributed to MSC-mediated drug resistance. In contrast, blocking the Wnt pathway led to decreased ALL cell viability. Chemotherapy plus the β-catenin inhibitor XAV939 resulted in a decreased tumor burden and improved overall survival in an ALL mouse model compared with chemotherapy alone. Our data demonstrate that targeting the Wnt pathway may represent an innovative approach to the treatment of ALL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE36372 | GEO | 2014/01/01

SECONDARY ACCESSION(S): PRJNA153247

REPOSITORIES: GEO

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Wnt Pathway Contributes to the Protection of Acute Lymphoblastic Leukemia Cells by Bone Marrow Stromal Cells and May Be a Therapeutic Target

Project description:Acute lymphoblastic leukemia (ALL) is the most common cancer in children and one of the most common cancers in adults. Although most children with ALL can be cured, approximately 60% of adults with ALL develop drug resistance or experience relapse and cannot be cured with traditional chemotherapy. One possible reason that treatment fails to eradicate ALL cells is that residual leukemia cells are protected by various components of the bone marrow microenvironment, such as marrow stromal cells (MSCs). To evaluate the effects of MSCs on ALL cell survival and response to chemotherapy, we co-cultured ALL cells with human or murine MSCs. We found that both human and murine MSCs protected human ALL cell lines and primary ALL cells from spontaneous and Ara-C-induced apoptosis. MSCs also modulated the cell cycle and increased ALL cell proliferation. Specifically, we found that Wnt signaling activation contributed to MSC-mediated drug resistance. In contrast, blocking the Wnt pathway led to decreased ALL cell viability. Chemotherapy plus the β-catenin inhibitor XAV939 resulted in a decreased tumor burden and improved overall survival in an ALL mouse model compared with chemotherapy alone. Our data demonstrate that targeting the Wnt pathway may represent an innovative approach to the treatment of ALL. Reh cells were harvested after being treated with Ara-C for 48 hours, with or without HS and HS-5 human stromal cells. Independent triplicate samples were used in the experiments. Total RNA was prepared using TRI reagent (Ambion, Austin, TX) and amplification and synthesis of cRNA was performed using Illumina TotalPrep RNA amplification kit (Ambion). cRNA was then hybridized to the HumanHT-12 v3 Expression BeadChip (Illumina, San Diego, CA) according to the manufacturer's instructions.

2014-01-01 | E-GEOD-36372 | biostudies-arrayexpress

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Inhibition of the Wnt/β-catenin signaling pathway and SOX9 by XAV939 does not alleviate inflammation in a dextran sulfate sodium-induced ulcerative colitis model

Project description:The Wnt/β-catenin signaling pathway is known to be hyperactivated during the pathogenesis of ulcerative colitis (UC). The present study aimed to explore the therapeutic efficacy of the Wnt/β-catenin signaling inhibitor XAV939 in mitigating UC symptoms. Utilizing a dextran sulfate sodium (DSS)-induced UC mouse model, the present study aimed to evaluate the impact of XAV939 on intestinal morphology through H&E staining and to measure the expression levels of critical proteins in the Wnt/β-catenin signaling cascade. XAV939 did not exert a significant influence on the morphological features and inflammatory status of the intestinal epithelium. However, XAV939 was found to effectively suppress the Wnt/β-catenin signaling pathway and its downstream target SOX9. This suppression implies a reduction in the differentiation of intestinal stem cells into secretory cell progenitor cells. Additionally, XAV939 was ineffective in reversing the DSS-induced derease in Villin and peroxisome proliferator-activated receptor γ, suggesting that it did not facilitate the differentiation of intestinal absorptive cells. The present findings indicated that the Wnt/β-catenin signaling pathway may not be the predominant mechanism in the pathogenesis of DSS-induced UC.

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