title: Increased CCL2 and IL-8 in the bone marrow microenvironment in acute lymphoblastic leukemia.
abstract: BACKGROUND
  The interactions of acute lymphoblastic leukemia (ALL) blasts with bone marrow (BM) stromal cells have a positive impact on leukemia cell survival. In the present study, we proposed to identify and investigate the role of molecules critically involved in leukemia--microenvironment crosstalk.
  
  
  METHODS
  Gene expression profiling analyses of BM mesenchymal stem cells (BMMSC) were performed following stimulation by ALL cells. CCL2 and IL-8 plasma levels were evaluated from ALL patients and controls. Expression of the CCL2 and IL-8 receptors in ALL was determined by RT-PCR. The biological effects of CCL2, IL-8 or its neutralizing antibodies in primary precursor-B ALL and BMMSC cells were evaluated using in vitro assays.
  
  
  RESULTS
  Leukemia stimulation of BMMSC upregulated the expression of several inflammatory chemokines, including CCL2 and IL-8. The BM plasma levels of CCL2 and IL-8 in children at diagnosis were significantly higher than in healthy controls (P < 0.001). Functional studies revealed that CCL2 and IL-8 enhanced the capacity of BMMSC to support adhesion of ALL cells. CCL2 and IL-8 were also found to enhance BMMSC survival and to increase their proliferation. ALL cells were not directly affected by CCL2 or IL-8.
  
  
  CONCLUSIONS
  The leukemic BM microenvironment had increased levels of CCL2 and IL-8. These chemokines are known to have suppressive effects in normal hematopoiesis. Our data indicate that CCL2 and IL-8 have a positive impact on BMMSC survival, proliferation, and adhesiveness to ALL cells. Leukemia-associated CCL2 and IL-8 upregulation may represent one possible mechanism of microenvironment perversion in favor of ALL cells.
authors.affiliation: Molecular Biology Laboratory, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors.forename: Jaíra Ferreira
authors.initials: JF
authors.lastname: de Vasconcellos
authors.forename: Angelo Brunelli Albertoni
authors.initials: AB
authors.lastname: Laranjeira
authors.forename: Nilson Ivo Tonin
authors.initials: NI
authors.lastname: Zanchin
authors.forename: Rosemary
authors.initials: R
authors.lastname: Otubo
authors.forename: Thais Haline
authors.initials: TH
authors.lastname: Vaz
authors.forename: Angelo Almeida
authors.initials: AA
authors.lastname: Cardoso
authors.forename: Silvia Regina
authors.initials: SR
authors.lastname: Brandalise
authors.forename: José Andrés
authors.initials: JA
authors.lastname: Yunes
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism*; D002448:Cell Adhesion; D002470:Cell Survival; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D016209:Interleukin-8 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D011379:Prognosis; D015398:Signal Transduction
chemical_list: D018932:Chemokine CCL2; D016209:Interleukin-8