Mesenchymal COX2-PG secretome engages NR4A-WNT signalling axis in haematopoietic progenitors to suppress anti-leukaemia immunity.
Limei WuSurya AmarachinthaJian XuFrank OleyWei DuPublished in: British journal of haematology (2018)
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-2γ-/- /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/β-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.
Keyphrases
- bone marrow
- acute myeloid leukemia
- stem cells
- induced apoptosis
- mesenchymal stem cells
- endothelial cells
- cell proliferation
- cell cycle arrest
- dendritic cells
- oxidative stress
- transcription factor
- genome wide
- mass spectrometry
- type diabetes
- metabolic syndrome
- allogeneic hematopoietic stem cell transplantation
- poor prognosis
- squamous cell carcinoma
- adipose tissue
- signaling pathway
- copy number
- weight loss
- epithelial mesenchymal transition
- dna methylation
- immune response
- acute lymphoblastic leukemia
- umbilical cord
- atomic force microscopy
- single molecule
- obese patients
- drug induced
- induced pluripotent stem cells
- squamous cell
- high resolution mass spectrometry