title: Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1 low mouse model of the disease.
abstract: OBJECTIVE
  To assess whether alterations in the stromal cell-derived factor-1 (SDF-1)/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1 low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking.
  
  
  METHODS
  In the mouse, SDF-1 mRNA levels were assayed in liver, spleen, and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients.
  
  
  RESULTS
  In Gata1 low mice, the plasma SDF-1 protein was five times higher than normal in younger animals. Furthermore, SDF-1 immunostaining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, plasma SDF-1 levels in PMF patients were significantly higher (by twofold) than normal (p < 0.01) and SDF-1 immunostaining of marrow biopsy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similar to what already has been reported for PMF patients, the marrow from Gata1 low mice contained fewer CXCR4 pos CD117 pos cells and these cells expressed low levels of CXCR4 mRNA and protein.
  
  
  CONCLUSIONS
  Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1 low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF.
authors.affiliation: Departments of Hematology, Oncology and Molecular Medicine, Istituto Superiore Sanità, Rome, Italy. migliar@iss.it
authors.forename: Anna Rita
authors.initials: AR
authors.lastname: Migliaccio
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Martelli
authors.forename: Maria
authors.initials: M
authors.lastname: Verrucci
authors.forename: Giovanni
authors.initials: G
authors.lastname: Migliaccio
authors.forename: Alessandro Maria
authors.initials: AM
authors.lastname: Vannucchi
authors.forename: Hongyu
authors.initials: H
authors.lastname: Ni
authors.forename: Mingjiang
authors.initials: M
authors.lastname: Xu
authors.forename: Yi
authors.initials: Y
authors.lastname: Jiang
authors.forename: Betty
authors.initials: B
authors.lastname: Nakamoto
authors.forename: Thalia
authors.initials: T
authors.lastname: Papayannopoulou
authors.forename: Ronald
authors.initials: R
authors.lastname: Hoffman
mesh_terms: D000367:Age Factors; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009928:Organ Specificity / Q000235:genetics; D055728:Primary Myelofibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous
chemical_list: C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494689:Gata1 protein, mouse; D019718:Receptors, CXCR4