title: Chronic lymphocytic leukemia cells induce anti-apoptotic effects of bone marrow stroma.
abstract: The prolonged life span of chronic lymphocytic leukemia (CLL) cells in vivo is assumed to depend on the surrounding microenvironment since this biologic feature is lost in vitro. We studied here the molecular interactions between CLL cells and their surrounding stroma to identify factors that help CLL cells to resist apoptosis. Sorted CLL cells from 21 patients were cultured in vitro on allogenous, normal bone marrow stromal cells (BMSCs) in the presence/absence of CD40 ligand or in culture medium alone. Surface and mRNA expression of interaction molecules, cytokine production, and apoptosis rate was measured by flow cytometric, real-time PCR and standard immunologic assays. The interaction between CLL cells and BMSCs rescued CLL cells from apoptosis. BMSCs co-cultured with CLL cells showed a strong increase in IL-8 and IL-6 secretion and up-regulated the expression of ICAM-1 and CD40 mRNA. The mRNA expression of CXCL12 and VCAM1 remained unchanged. In turn, CLL cells in interaction with BMSCs significantly up-regulated the expression of CD18 and CD49d that are ligands for the critical adhesion molecules on BMSCs. As a validation of the in vitro data, we found a significant higher expression of CD49d on CLL cells in bone marrow aspirates compared to peripheral blood CLL cells in patient samples. Up-regulation of adhesion molecules and their ligands in CLL-BMSCs interaction along with the increased cytokine production of BMSCs indicate a strong effect of CLL cells on BMSCs in favor of their apoptosis resistance.
authors.affiliation: Institute of Pathology, University of Regensburg, 93053, Regensburg, Germany.
authors.forename: Márk
authors.initials: M
authors.lastname: Plander
authors.forename: Peter
authors.initials: P
authors.lastname: Ugocsai
authors.forename: Silvia
authors.initials: S
authors.lastname: Seegers
authors.forename: Evelyn
authors.initials: E
authors.lastname: Orsó
authors.forename: Albrecht
authors.initials: A
authors.lastname: Reichle
authors.forename: Gerd
authors.initials: G
authors.lastname: Schmitz
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Hofstädter
authors.forename: Gero
authors.initials: G
authors.lastname: Brockhoff
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D018821:CD18 Antigens / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D023201:CD40 Ligand / Q000494:pharmacology; D054377:Chemokine CXCL12 / Q000378:metabolism; D018920:Coculture Techniques; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D039441:Integrin alpha4 / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology*; D014407:Tumor Cells, Cultured; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D018821:CD18 Antigens; D019013:CD40 Antigens; D054377:Chemokine CXCL12; D015850:Interleukin-6; D016209:Interleukin-8; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D039441:Integrin alpha4; D023201:CD40 Ligand