title: Bone marrow mesenchymal stromal cells non-selectively protect chronic myeloid leukemia cells from imatinib-induced apoptosis via the CXCR4/CXCL12 axis.
abstract: BACKGROUND
  Residual chronic myeloid leukemia disease following imatinib treatment has been attributed to the presence of quiescent leukemic stem cells intrinsically resistant to imatinib. Mesenchymal stromal cells in the bone marrow may favor the persistence and progression of leukemia by preserving the proliferation and self-renewal capacities of the malignant progenitor cells.
  
  
  METHODS
  BV173 or primary chronic myeloid leukemia cells were co-cultured with human mesenchymal stromal cells and imatinib-induced cell death was then measured. The roles of pro-and anti-apoptotic proteins and chemokine CXCL12 in this context were evaluated. We also studied the ability of BV173 cells to repopulate NOD/SCID mice following in vitro exposure to imatinib and mesenchymal stromal cells.
  
  
  RESULTS
  Whilst imatinib induced dose-dependent apoptosis of BV173 cells and primary chronic myeloid leukemia cells, co-culture with mesenchymal stromal cells protected both types of chronic myeloid leukemia cells. Molecular analysis indicated that mesenchymal stromal cells reduced caspase-3 activation and modulated the expression of the anti-apoptotic protein Bcl-XL. Furthermore, chronic myeloid leukemia cells exposed to imatinib in the presence of mesenchymal stromal cells retained the ability to engraft into NOD/SCID mice. We observed that chronic myeloid leukemia cells and mesenchymal stromal cells express functional levels of CXCR4 and CXCL12, respectively. Finally, the CXCR4 antagonist, AMD3100 restored apoptosis by imatinib and the susceptibility of the SCID leukemia repopulating cells to the tyrosine kinase inhibitor.
  
  
  CONCLUSIONS
  Human mesenchymal stromal cells mediate protection of chronic myeloid leukemia cells from imatinib-induced apoptosis. Disruption of the CXCL12/CXCR4 axis restores, at least in part, the leukemic cells' sensitivity to imatinib. The combination of anti-CXCR4 antagonists with tyrosine kinase inhibitors may represent a powerful approach to the treatment of chronic myeloid leukemia.
authors.affiliation: Department of Haematology, Kennedy Institute of Rheumatology, Imperial College, London, UK.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Vianello
authors.forename: Federica
authors.initials: F
authors.lastname: Villanova
authors.forename: Veronica
authors.initials: V
authors.lastname: Tisato
authors.forename: Stefania
authors.initials: S
authors.lastname: Lymperi
authors.forename: Ka-Kei
authors.initials: KK
authors.lastname: Ho
authors.forename: Ana R
authors.initials: AR
authors.lastname: Gomes
authors.forename: David
authors.initials: D
authors.lastname: Marin
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.forename: Jane
authors.initials: J
authors.lastname: Apperley
authors.forename: Eric W-F
authors.initials: EW
authors.lastname: Lam
authors.forename: Francesco
authors.initials: F
authors.lastname: Dazzi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001549:Benzamides; D001854:Bone Marrow Cells; D054377:Chemokine CXCL12 / Q000502:physiology; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000502:physiology; D017154:Stromal Cells; D014407:Tumor Cells, Cultured
chemical_list: D001549:Benzamides; D054377:Chemokine CXCL12; D010879:Piperazines; D011743:Pyrimidines; D019718:Receptors, CXCR4; D000068877:Imatinib Mesylate