title: Impact of CXCR4 inhibition on FLT3-ITD-positive human AML blasts.
abstract: OBJECTIVE
  Internal tandem duplication (ITD) mutations of the FLT3 receptor are associated with a high incidence of relapse in acute myeloid leukemia (AML). Expression of the CXCR4 receptor in FLT3-ITD-positive AML is correlated with poor outcome, and inhibition of CXCR4 was shown to sensitize AML blasts toward chemotherapy. The aim of this study was to evaluate the impact of FLT3-ITD on cell proliferation and CXCR4-dependent migration in human hematopoietic progenitor cells and to investigate their response to CXCR4 inhibition.
  
  
  METHODS
  We used primary blasts from patients with FLT3-ITD or FLT3 wild-type AML. In addition, human CD34(+) hematopoietic progenitor cells were transduced to >70% with retroviral vectors containing human FLT3-ITD.
  
  
  RESULTS
  We found that FLT3-ITD transgene overexpressing human hematopoietic progenitor cells show strongly reduced migration toward stromal-derived factor-1 in vitro and display significantly reduced bone marrow homing in nonobese diabetic severe combined immunodeficient mice. Cocultivation of FLT3-ITD-positive AML blasts or hematopoietic progenitor cells on bone marrow stromal cells resulted in a strong proliferation advantage and increased early cobblestone area-forming cells compared to FLT3-wild-type AML blasts. Addition of the CXCR4 inhibitor AMD3100 to the coculture significantly reduced both cobblestone area-forming cells and proliferation of FLT3-ITD-positive cells, but did not affect FLT3-wild-type cells-highlighting the critical interaction between CXCR4 and FLT3-ITD.
  
  
  CONCLUSIONS
  CXCR4 inhibition to decrease cell proliferation and to control the leukemic burden may provide a novel therapeutic strategy in patients with advanced FLT3-ITD-positive AML.
authors.affiliation: Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Dresden, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Jacobi
authors.forename: Sebastian
authors.initials: S
authors.lastname: Thieme
authors.forename: Romy
authors.initials: R
authors.lastname: Lehmann
authors.forename: Fernando
authors.initials: F
authors.lastname: Ugarte
authors.forename: Harry L
authors.initials: HL
authors.lastname: Malech
authors.forename: Sina
authors.initials: S
authors.lastname: Koch
authors.forename: Christian
authors.initials: C
authors.lastname: Thiede
authors.forename: Katrin
authors.initials: K
authors.lastname: Müller
authors.forename: Martin
authors.initials: M
authors.lastname: Bornhäuser
authors.forename: Martin
authors.initials: M
authors.lastname: Ryser
authors.forename: Sebastian
authors.initials: S
authors.lastname: Brenner
mesh_terms: D000208:Acute Disease; D000818:Animals; D001596:Benzylamines; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D000080027:Cyclams; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D007942:Leukemia, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D014183:Transplantation, Heterologous; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001596:Benzylamines; C527276:CXCR4 protein, human; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C088327:plerixafor