Mesenchymal <scp>COX</scp>2‐<scp>PG</scp> secretome engages <scp>NR</scp>4A‐<scp>WNT</scp> signalling axis in haematopoietic progenitors to suppress anti‐leukaemia immunity

Wu, Limei; Amarachintha, Surya; Xu, Jian; Oley, Frank; Du, Wei

doi:10.1111/bjh.15548

Cited by 33 publications

(36 citation statements)

References 65 publications

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“…As one of the predicted targets of TW for the treatment of AML, PTGS2 can be acted by 7 active compounds in TW. It has been reported that it can selectively inhibit cox-2 and play a role in the treatment of AML (36)(37)(38) . This means that multiple active ingredients in traditional Chinese medicine can act on a single target to take effect in the treatment of diseases.…”

Section: Discussionmentioning

confidence: 99%

“…This indicates that Tripterygium wilfordii may have multiple active ingredients through multiple pathways to prevent and treat AML. Such as Toll-like receptor signaling pathway, as a part of the innate immune system, studies have shown that various hematological malignant cells, including AML cells, express TLRs, and TLR agonists may directiy effect on the leukemic cells (38) . Due to the indirect anti-leukemia effect caused by the activation / stimulation of normal immuneocompetent cells, such as eradicating residual leukemia cells after induction therapy, TLR is considered a possible drug target in AML (42) .…”

Section: Discussionmentioning

confidence: 99%

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Network Pharmacology-Based Strategy for Predicting Therapy Targets of Tripterygium wilfordii on Acute Myeloid Leukemia

Fang

Liu

Chen

2020

Preprint

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Background. Acute myeloid leukemia (AML) is a common malignant tumor of the hematopoietic system. How to extend the survival time of AML patients and improve their prognosis is still a major medical problem. Chinese medicine has a long history in treating AML. Tripterygium wilfordii (TW) is a traditional Chinese medicine. With the deepening of pharmacological research of traditional Chinese medicine, triptolide, one of its active ingredients, has been proven to have a positive effect on the treatment of AML. Therefore，this study aimed on studying the potential therapeutic targets and pharmacological mechanism of TW in Acute myeloid leukemia (AML) based on network pharmacology.Methods. The active components of TW were obtained by network pharmacology through oral bioavailability, drug-likeness filtration. Comparative analysis was used to study the overlapping genes between active ingredient’s targets and AML treatment-related targets. Using STRING database to analyze interactions between overlapping genes. KEGG pathway analysis and Gene Ontology enrichment analysis were conducted in DAVID. These genes were analyzed for survival in OncoLnc database.Key findings. We screened 53 active ingredients, the results of comparative analysis showed that 8 active ingredients had an effect on AML treatment. Based on the active ingredients and overlapping genes, we constructed the Drug-Compounds-Genes-Disease Network. Survival analysis of overlapping genes indicated that some targets possess a significant influence on patients’ survival and prognosis. The enrichment analysis showed that the main pathways of targets are Toll-like receptor signaling pathway, NF-kappa B signaling pathway and HIF-1 signaling pathway.Conclusion. This study, using a network pharmacologic approach, provides another strategy that can help us to understand the mechanisms by which TW treats AML comprehensively.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-Based Strategy for Predicting Therapy Targets of Tripterygium wilfordii on Acute Myeloid Leukemia

Fang

Liu

Chen

2020

Preprint

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“…In a study on the interaction between hematopoietic stem and progenitor cells (HSPCs) and leukaemia mesenchymal niche, mesenchymal stromal cells (MSCs) derived from Fanconi anaemia (FA) patients with acute myeloid leukaemia (AML) (FA-AML MSCs) promoted expansion of healthy donor HSPCs, myeloid expansion of bone marrow CD34 + cells, and Treg differentiation. The HSPC/myeloid expansion is mediated by leukemic mesenchymal COX-2-prostaglandin (PG) secretome [ 85 ]. Three pathways have been identified that mediate the effect of the COX-2 PG secretome: (i) NR4A2 signaling, (ii) Wnt signaling, and (iii) Treg function pathways.…”

Section: Nurr1 and Inhibition Of Antitumor Immunitymentioning

confidence: 99%

“…Downregulation of PG by COX-2 inhibition ameliorates HSPC/myeloid expansions and reduces expression of NR4A and expression of Treg genes (Foxp3 and CTLA-4) in AML MSCs cocultured with CD34 + populations, indicating an association between the COX2-PG secretome and NR4A-Treg signaling [ 85 ]. In addition, Nurr1 and Nur77 act synergistically on the promoter of proto-oncogene β-catenin (CTNNB1) to enhance Wnt activation [ 85 ]. CTNNB1 knockdown significantly upregulates CD8 + CCR7 + T effector cells, an important subset in anti-leukemia immunity, without affecting the Treg population.…”

Section: Nurr1 and Inhibition Of Antitumor Immunitymentioning

confidence: 99%

Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review

Wan

Siu

Leung

et al. 2020

Cancers

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Nuclear receptor related-1 protein (Nurr1), coded by an early response gene, is involved in multiple cellular and physiological functions, including proliferation, survival, and self-renewal. Dysregulation of Nurr1 has been frequently observed in many cancers and is attributed to multiple transcriptional and post-transcriptional mechanisms. Besides, Nurr1 exhibits extensive crosstalk with many oncogenic and tumor suppressor molecules, which contribute to its potential pro-malignant behaviors. Furthermore, Nurr1 is a key player in attenuating antitumor immune responses. It not only potentiates immunosuppressive functions of regulatory T cells but also dampens the activity of cytotoxic T cells. The selective accessibility of chromatin by Nurr1 in T cells is closely associated with cell exhaustion and poor efficacy of cancer immunotherapy. In this review, we summarize the reported findings of Nurr1 in different malignancies, the mechanisms that regulate Nurr1 expression, and the downstream signaling pathways that Nurr1 employs to promote a wide range of malignant phenotypes. We also give an overview of the association between Nurr1 and antitumor immunity and discuss the inhibition of Nurr1 as a potential immunotherapeutic strategy.

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“…Therefore, despite advancements in our understanding of the molecular and genetic alterations in AML, the abnormalities in BM-MSCs derived from AML patients (AML-MSCs) have not been fully elucidated. AML-MSCs overexpress several chemokines and cytokines, such as stromal cell-derived factor-1 (SDF-1, also known as CXCL12) 9 , prostaglandins (PGs) 10 , galectin 3 11 , apoptosis repressor with caspase recruitment domain (ARC) protein 12 , and IL-10 13 and were more prefer to support LC survival compared with normal MSCs. Proteomic profiling has also revealed a different protein expression profile of AML-MSCs, and certain MSC protein expression signatures may be related to patient survival and remission 11 .…”

Section: Introductionmentioning

confidence: 99%

Co-culture with leukemia cells decreases proliferation and increases chemoprotective capacity of normal mesenchymal stromal cells

Hou¹,

Yang²,

Zhang³

et al. 2020

Preprint

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Background Bone marrow mesenchymal stromal cells (BM-MSCs) are essential structural and functional components of the BM microenvironment and play an important role in acute myeloid leukemia (AML) pathogenesis. BM-MSCs isolated from AML patients (AML-MSCs) show distinct signatures from normal BM-MSCs. However, the exact abnormalities of AML-MSCs and the origin of these abnormalities are still unknown.Methods In this study, we evaluated the proliferative activity of AML-MSCs, and the influence of leukemia cells (LCs) on BM-MSCs. These two cell types were co-cultured using an in vitro co-culture system, and the biological functions of AML-MSCs, healthy donor derived MSCs (HD-MSCs), and LC-treated HD-MSCs (LCtrHD-MSCs) were compared by flow cytometry, and CCK-8 and chemotaxis assays. Student t-test (between two groups) and one-way ANOVA (more than 2 groups) were used to compare differences. Pearson correlation coefficients were used to assess correlations between two factors.Results AML-MSCs display a significant proliferative deficiency, which correlates with primary leukemic blast cell counts but not with patients’ age. Inhibition of BM-MSC proliferation could be induced by leukemia cells through direct contact. Co-cultured leukemia cells also increase expression of several inflammatory cytokines, and chemokines in BM-MSCs. Furthermore, LCtrHD-MSCs reduced apoptosis, and increased migration and chemoresistance in co-cultured AML cells, comparable with AML-MSCs.Conclusions Our results showed that leukemia cells can induce healthy donor derived BM-MSCs to exhibit AML-MSC-like characteristics and indicated that AML-MSC abnormalities may be partly induced by leukemia cells.

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Mesenchymal COX2‐PG secretome engages NR4A‐WNT signalling axis in haematopoietic progenitors to suppress anti‐leukaemia immunity

Cited by 33 publications

References 65 publications

Network Pharmacology-Based Strategy for Predicting Therapy Targets of Tripterygium wilfordii on Acute Myeloid Leukemia

Network Pharmacology-Based Strategy for Predicting Therapy Targets of Tripterygium wilfordii on Acute Myeloid Leukemia

Role of Nurr1 in Carcinogenesis and Tumor Immunology: A State of the Art Review

Co-culture with leukemia cells decreases proliferation and increases chemoprotective capacity of normal mesenchymal stromal cells

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