title: [Role of CXCR4/STAT3 in mesenchymal stromal cell-mediated drug resistance of acute leukemia cells].
abstract: OBJECTIVE
  To explore the role of CXCR4/STAT3 in mesenchymal stromal cell (MSC)-mediated drug resistance of AML cells.
  
  
  METHODS
  AML cell lines U937 and KG1a and primary AML cells were co-cultured with MSC from bone marrow of healthy donors. The AML cell lines cultured alone were used as control. Apoptosis induced by mitoxantrone was measured by flow cytometry. Expression of CXCR4 and STAT3 protein were detected by Western blot. After incubated with STAT3 inhibitor Cucurbitacin I or CXCR4 antagonist AMD3100, the apoptosis of AML cells induced by mitoxantrone was evaluated.
  
  
  RESULTS
  Apoptosis of AML cells (U937 and KG1a) and primary AML cells induced by mitoxantrone significantly decreased in cocultured group than that of control group [U937 cells: (20.08±1.53)% vs (45.33 ± 1.03)% , P=0.004; KG1a cells: (25.60 ± 1.82)% vs (40.33 ± 3.29)% , P=0.020]. Expression of phosphorylated STAT3 and CXCR4 protein in AML cells were upregulated in cocultured group. After addition of Cucurbitacin I into the co-culture system, the apoptosis rate of primary AML cells significantly increased. Similar results of the apoptosis rates were also detected when the inhibitor of CXCR4 AMD3100 was added to overcome the stromal cell-mediated drug resistance. Besides, the expression of p-STAT3 in AML cells after incubated with AMD3100 decreased significantly.
  
  
  CONCLUSIONS
  AML cells cocultured with MSC leads to the up-regulation of phosphorylated STAT3 and CXCR4 proteins, which resulted in AML cells resistance to chemotherapeutic drugs. Therefore targeting STAT3 or CXCR4 could be a new therapeutic strategy of AML.
authors.affiliation: Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center For Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China.
authors.forename: Yungjun
authors.initials: Y
authors.lastname: Tang
authors.forename: Qing
authors.initials: Q
authors.lastname: Guo
authors.forename: Yaqin
authors.initials: Y
authors.lastname: Zhi
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.forename: Bing
authors.initials: B
authors.lastname: Xia
authors.forename: Shanqi
authors.initials: S
authors.lastname: Guo
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.forename: Yizhuo
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000208:Acute Disease; D017209:Apoptosis; D001596:Benzylamines; D018920:Coculture Techniques; D000080027:Cyclams; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D015973:Gene Expression Regulation, Leukemic; D006571:Heterocyclic Compounds; D006801:Humans; D007938:Leukemia / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D020298:U937 Cells; D015854:Up-Regulation
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C088327:plerixafor