LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1.
Alexander Frederik Vom SteinRocio Rebollido-RiosAnna LukasMaximilian KochAnton von LomSebastian ReinartzDaniel BachurskiFrance RoseKatarzyna BozekAli T AbdallahViktoria KohlhasJulia SaggauRebekka ZölzerYue ZhaoChristiane BrunsPaul J BröckelmannPhilipp LohneisReinhard ButtnerBjörn HäuplThomas OellerichPhuong-Hien NguyenMichael HallekPublished in: Nature communications (2023)
Microenvironmental bystander cells are essential for the progression of chronic lymphocytic leukemia (CLL). We have discovered previously that LYN kinase promotes the formation of a microenvironmental niche for CLL. Here we provide mechanistic evidence that LYN regulates the polarization of stromal fibroblasts to support leukemic progression. LYN is overexpressed in fibroblasts of lymph nodes of CLL patients. LYN-deficient stromal cells reduce CLL growth in vivo. LYN-deficient fibroblasts show markedly reduced leukemia feeding capacity in vitro. Multi-omics profiling reveals that LYN regulates the polarization of fibroblasts towards an inflammatory cancer-associated phenotype through modulation of cytokine secretion and extracellular matrix composition. Mechanistically, LYN deletion reduces inflammatory signaling including reduction of c-JUN expression, which in turn augments the expression of Thrombospondin-1, which binds to CD47 thereby impairing CLL viability. Together, our findings suggest that LYN is essential for rewiring fibroblasts towards a leukemia-supportive phenotype.
Keyphrases
- extracellular matrix
- chronic lymphocytic leukemia
- acute myeloid leukemia
- bone marrow
- lymph node
- poor prognosis
- oxidative stress
- newly diagnosed
- ejection fraction
- public health
- induced apoptosis
- single cell
- tyrosine kinase
- protein kinase
- binding protein
- long non coding rna
- fluorescent probe
- patient reported outcomes
- wild type
- free survival
- nk cells