title: The tyrosine kinase inhibitor dasatinib induces a marked adipogenic differentiation of human multipotent mesenchymal stromal cells.
abstract: BACKGROUND
  The introduction of specific BCR-ABL inhibitors in chronic myelogenous leukemia therapy has entirely mutated the prognosis of this hematologic cancer from being a fatal disorder to becoming a chronic disease. Due to the probable long lasting treatment with tyrosine-kinase inhibitors (TKIs), the knowledge of their effects on normal cells is of pivotal importance.
  
  
  METHODS
  We investigated the effects of dasatinib treatment on human bone marrow-derived mesenchymal stromal cells (MSCs).
  
  
  RESULTS
  Our findings demonstrate, for the first time, that dasatinib induces MSCs adipocytic differentiation. Particularly, when the TKI is added to the medium inducing osteogenic differentiation, a high MSCs percentage acquires adipocytic morphology and overexpresses adipocytic specific genes, including PPARγ, CEBPα, LPL and SREBP1c. Dasatinib also inhibits the activity of alkaline phosphatase, an osteogenic marker, and remarkably reduces matrix mineralization. The increase of PPARγ is also confirmed at protein level. The component of osteogenic medium required for dasatinib-induced adipogenesis is dexamethasone. Intriguingly, the increase of adipocytic markers is also observed in MSCs treated with dasatinib alone. The TKI effect is phenotype-specific, since fibroblasts do not undergo adipocytic differentiation or PPARγ increase.
  
  
  CONCLUSIONS
  Our data demonstrate that dasatinib treatment affects bone marrow MSCs commitment and suggest that TKIs therapy might modify normal phenotypes with potential significant negative consequences.
authors.affiliation: Department of Biochemistry and Biophysics, Second University of Naples, Naples, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Borriello
authors.forename: Ilaria
authors.initials: I
authors.lastname: Caldarelli
authors.forename: Maria Assunta
authors.initials: MA
authors.lastname: Basile
authors.forename: Debora
authors.initials: D
authors.lastname: Bencivenga
authors.forename: Annunziata
authors.initials: A
authors.lastname: Tramontano
authors.forename: Silverio
authors.initials: S
authors.lastname: Perrotta
authors.forename: Fulvio
authors.initials: F
authors.lastname: Della Ragione
authors.forename: Adriana
authors.initials: A
authors.lastname: Oliva
mesh_terms: D017667:Adipocytes / Q000166:cytology*; D050156:Adipogenesis / Q000187:drug effects; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D000069439:Dasatinib; D006801:Humans; D020014:K562 Cells; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008648:Mesoderm / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy; D010006:Osteoblasts / Q000166:cytology; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000494:pharmacology*; D017154:Stromal Cells / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D000069439:Dasatinib