Differential bone marrow homing capacity of VLA-4 and CD38 high expressing chronic lymphocytic leukemia cells

• Published in: PloS one 2011-08, Vol.6 (8), p.e23758-e23758
• Main Authors: Brachtl, Gabriele, Sahakyan, Karine, Denk, Ursula, Girbl, Tamara, Alinger, Beate, Hofbauer, Sebastian W, Neureiter, Daniel, Hofbauer, Josefina Piñón, Egle, Alexander, Greil, Richard, Hartmann, Tanja Nicole
• Format: Article
• Language: English
• Subjects: Adhesion tests; Adoptive transfer; ADP-ribosyl Cyclase 1 - blood; ADP-ribosyl Cyclase 1 - metabolism; Animals; Antigens; Apoptosis; B cells; B-Lymphocytes - immunology; Bone marrow; Bone Marrow - metabolism; Bone Marrow - pathology; Cancer; CD38 antigen; Cell Adhesion; Cell adhesion & migration; Cell Count; Cell culture; Cell interactions; Chronic lymphocytic leukemia; Female; Hematology; Homing; Humans; Immunohistochemistry; Immunology; Infiltration; Infiltration (Hydrology); Infiltration rate; Integrin alpha4beta1 - blood; Integrin alpha4beta1 - metabolism; Ki-67 Antigen - metabolism; Laboratories; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell - blood; Leukemia, Lymphocytic, Chronic, B-Cell - metabolism; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemic Infiltration - pathology; Lymphatic leukemia; Lymphocyte receptors; Lymphoid Tissue - pathology; Male; Medical research; Medicine; Mice; Multiple sclerosis; Oncology; Pathogenesis; Pathology; Patients; Peripheral blood; Prognosis; Rheumatology; Risk; Risk Factors; Stromal cells; Stromal Cells - pathology; Subpopulations; Survival Analysis; VLA-4 antigen
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0023758

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. 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. 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. 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.