title: Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells.
abstract: BACKGROUND
  VLA-4 and CD38 predict a poor clinical outcome in chronic lymphocytic leukemia (CLL). We used CLL samples with discordant VLA-4/CD38 risk to address their individual roles in human bone marrow infiltration (BM), CLL cell homing to murine BM, and in supportive CLL cell-stromal cell interactions.
  
  
  METHODS
  VLA-4, CD38, and Ki-67 expression was measured in CLL cells from peripheral blood (PB) and bone marrow (BM) aspirates. CLL BM infiltration rates, routinely determined by Pathology, were correlated to VLA-4 and CD38 expression. Short-term homing capacity of CLL cells was evaluated by adoptive transfer experiments. CLL cell viability and adhesion in stromal cell co-culture was determined.
  
  
  RESULTS
  About 20% of CLL samples in our cohort displayed discordant VLA-4 and CD38 risk, with either high VLA-4 and low CD38 risk or vice versa. Using particularly such samples, we observed that VLA-4, and not CD38, was responsible for recirculation of CLL cells to murine BM. Human BM infiltration was also significantly higher in patients with high VLA-4 risk but not high CD38 risk. However, both molecules acted as independent prognostic markers. While both VLA-4 and CD38 expression were increased in BM-derived CLL cells, and VLA-4+ and CD38+ subpopulations showed enriched Ki-67 expression, VLA-4 did not contribute to CLL cell protection by stromal cells in vitro.
  
  
  CONCLUSIONS
  Our data argue for a prominent role of VLA-4 but not CD38 expression in the homing of CLL cells to BM niches and in human BM infiltration, but only a limited role in their protection by stromal cells.
authors.affiliation: Laboratory for Immunological and Molecular Cancer Research, Third Medical Department with Hematology, Oncology, Hemostaseology, Infectiology and Rheumatology, Private Medical University Hospital, Salzburg, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Brachtl
authors.forename: Karine
authors.initials: K
authors.lastname: Sahakyan
authors.forename: Ursula
authors.initials: U
authors.lastname: Denk
authors.forename: Tamara
authors.initials: T
authors.lastname: Girbl
authors.forename: Beate
authors.initials: B
authors.lastname: Alinger
authors.forename: Sebastian W
authors.initials: SW
authors.lastname: Hofbauer
authors.forename: Daniel
authors.initials: D
authors.lastname: Neureiter
authors.forename: Josefina Piñón
authors.initials: JP
authors.lastname: Hofbauer
authors.forename: Alexander
authors.initials: A
authors.lastname: Egle
authors.forename: Richard
authors.initials: R
authors.lastname: Greil
authors.forename: Tanja Nicole
authors.initials: TN
authors.lastname: Hartmann
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000097:blood / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D002448:Cell Adhesion; D002452:Cell Count; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D039041:Integrin alpha4beta1 / Q000097:blood / Q000378:metabolism*; D019394:Ki-67 Antigen / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D017254:Leukemic Infiltration / Q000473:pathology*; D008221:Lymphoid Tissue / Q000473:pathology; D008297:Male; D051379:Mice; D012307:Risk Factors; D017154:Stromal Cells / Q000473:pathology; D016019:Survival Analysis
chemical_list: D039041:Integrin alpha4beta1; D019394:Ki-67 Antigen; D051997:ADP-ribosyl Cyclase 1