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

ABSTRACT: The bone marrow (BM) microenvironment (niche) plays important roles in supporting normal/abnormal haematopoiesis. We investigated the interaction between leukaemic mesenchymal niche and haematopoietic stem and progenitor cells (HSPCs) using the model of Fanconi anaemia (FA), a genetic disorder characterized by BM failure and leukaemia. Healthy donor HSPCs co-cultured on mesenchymal stromal cells (MSCs) derived from FA patients with acute myeloid leukaemia (AML) exhibited higher human engraftment and myeloid expansion in Non-obese diabetic severe combined immunodeficiency IL-2?-/- /SGM3 recipients. Untargeted metabolomics analysis revealed the progressively elevated prostaglandins (PGs) in the MSCs of FA patients with myelodysplastic syndromes (MDS) and AML. Reduced secretion of PGs subsequent to inflammatory cyclooxygenase 2 (COX2) inhibition ameliorated HSPC/myeloid expansion. Transcriptome analysis demonstrated dysregulation of genes involved in the NR4A family of transcription factors (TFs) and WNT/?-catenin signalling pathway in FA-AML-MSC-co-cultured-CD34+ cells. COX2 inhibition led to significantly decreased NR4A TFs and WNT signalling genes expression. Mechanistically, NR4A1 and NR4A2 synergistically activate the CTNNB1 gene promoter . Knocking down CTNNB1 or NR4A1 in AML-MSC-co-cultured-CD34+ cells increased leukaemia-reactive T-effector cells production and rescued anti-leukaemia immunity. Together, these findings suggest that specific interactions between leukaemic mesenchymal niche and HSPCs orchestrate a novel COX2/PG-NR4A/WNT signalling axis, connecting inflammation, cellular metabolism and cancer immunity.

SUBMITTER: Wu L

PROVIDER: S-EPMC6391996 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Wu Limei L Amarachintha Surya S Xu Jian J Oley Frank F Du Wei W

British journal of haematology 20180814 3

The bone marrow (BM) microenvironment (niche) plays important roles in supporting normal/abnormal haematopoiesis. We investigated the interaction between leukaemic mesenchymal niche and haematopoietic stem and progenitor cells (HSPCs) using the model of Fanconi anaemia (FA), a genetic disorder characterized by BM failure and leukaemia. Healthy donor HSPCs co-cultured on mesenchymal stromal cells (MSCs) derived from FA patients with acute myeloid leukaemia (AML) exhibited higher human engraftment ...[more]

PMID: 30106181

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Project description:Epigenetic modifications must underlie lineage-specific differentiation as terminally differentiated cells express tissue-specific genes, but their DNA sequence is unchanged. Haematopoiesis provides a well-defined model to study epigenetic modifications during cell-fate decisions, as multipotent progenitors (MPPs) differentiate into progressively restricted myeloid or lymphoid progenitors. Although DNA methylation is critical for myeloid versus lymphoid differentiation, as demonstrated by the myeloerythroid bias in Dnmt1 hypomorphs, a comprehensive DNA methylation map of haematopoietic progenitors, or of any multipotent/oligopotent lineage, does not exist. Here we examined 4.6 million CpG sites throughout the genome for MPPs, common lymphoid progenitors (CLPs), common myeloid progenitors (CMPs), granulocyte/macrophage progenitors (GMPs), and thymocyte progenitors (DN1, DN2, DN3). Marked epigenetic plasticity accompanied both lymphoid and myeloid restriction. Myeloid commitment involved less global DNA methylation than lymphoid commitment, supported functionally by myeloid skewing of progenitors following treatment with a DNA methyltransferase inhibitor. Differential DNA methylation correlated with gene expression more strongly at CpG island shores than CpG islands. Many examples of genes and pathways not previously known to be involved in choice between lymphoid/myeloid differentiation have been identified, such as Arl4c and Jdp2. Several transcription factors, including Meis1, were methylated and silenced during differentiation, indicating a role in maintaining an undifferentiated state. Additionally, epigenetic modification of modifiers of the epigenome seems to be important in haematopoietic differentiation. Our results directly demonstrate that modulation of DNA methylation occurs during lineage-specific differentiation and defines a comprehensive map of the methylation and transcriptional changes that accompany myeloid versus lymphoid fate decisions.

Dataset Information

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

Publications

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

Similar Datasets

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