title: Leukemia cells induce changes in human bone marrow stromal cells.
abstract: BACKGROUND
  Bone marrow stromal cells (BMSCs) are multipotent cells that support angiogenesis, wound healing, and immunomodulation. In the hematopoietic niche, they nurture hematopoietic cells, leukemia, tumors and metastasis. BMSCs secrete of a wide range of cytokines, growth factors and matrix proteins which contribute to the pro-tumorigenic marrow microenvironment. The inflammatory cytokines IFN-γ and TNF-α change the BMSC secretome and we hypothesized that factors produced by tumors or leukemia would also affect the BMSC secretome and investigated the interaction of leukemia cells with BMSCs.
  
  
  METHODS
  BMSCs from healthy subjects were co-cultured with three myeloid leukemia cell lines (TF-1, TF-1α and K562) using a trans-well system. Following co-culture, the BMSCs and leukemia cells were analyzed by global gene expression analysis and culture supernatants were analyzed for protein expression. As a control, CD34+ cells were also cocultured with BMSCs.
  
  
  RESULTS
  Co-culture induced leukemia cell gene expression changes in stem cell pluripotency, TGF-β signaling and carcinoma signaling pathways. BMSCs co-cultured with leukemia cells up-regulated a number of proinflammatory genes including IL-17 signaling-related genes and IL-8 and CCL2 levels were increased in co-culture supernatants. In contrast, purine metabolism, mTOR signaling and EIF2 signaling pathways genes were up-regulated in BMSCs co-cultured with CD34+ cells.
  
  
  CONCLUSIONS
  BMSCs react to the presence of leukemia cells undergoing changes in the cytokine and chemokine secretion profiles. Thus, BMSCs and leukemia cells both contribute to the creation of a competitive niche more favorable for leukemia stem cells.
authors.forename: Sara
authors.initials: S
authors.lastname: Civini
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.forename: Jiaqiang
authors.initials: J
authors.lastname: Ren
authors.forename: Marianna
authors.initials: M
authors.lastname: Sabatino
authors.forename: Luciano
authors.initials: L
authors.lastname: Castiello
authors.forename: Jianjian
authors.initials: J
authors.lastname: Jin
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Yuanlong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Francesco
authors.initials: F
authors.lastname: Marincola
authors.affiliation: Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health (NIH), Building 10, Room 3C720, 9000 Rockville Pike, Bethesda, MD 20892-1184, USA. DStroncek@cc.nih.gov.
authors.forename: David
authors.initials: D
authors.lastname: Stroncek
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology*; D018920:Coculture Techniques; D020869:Gene Expression Profiling; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*