title: Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1.
abstract: Chronic lymphocytic leukemia (CLL) B cells have defects in apoptosis pathways and therefore accumulate in vivo. However, when removed from the patient and cultured in vitro, these malignant cells rapidly undergo apoptosis. Recent studies suggest that leukemia cell survival is influenced by interactions with nonleukemia cells in the microenvironment of lymph nodes, marrow, and other tissues. To model such cell-cell interactions in vitro, we cultured freshly isolated CLL B cells with a follicular dendritic cell line, HK. CLL B cells cocultured with HK cells were protected from apoptosis, either spontaneous or induced by treatment with anticancer drugs. Protection against spontaneous apoptosis could also be induced by coculturing the CLL B cells with normal dendritic cells (DCs) or with a CD40-ligand (CD154)-expressing fibroblast cell line. Examination of the expression of several apoptosis-regulatory proteins revealed that coculture with HK cells or DCs induced up-regulation of the antiapoptotic Bcl-2 family protein Mcl-1 in CLL B cells, whereas CD40 ligation increased expression of Bcl-X(L). Cell-cell contact was required for HK-induced protection, and introducing neutralizing antibodies against various adhesion molecules showed that CD44 was involved in HK-mediated survival, whereas CD40, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were not. Anti-CD44 antibodies also blocked Mcl-1 induction by HK cells. Mcl-1 antisense oligonucleotides reduced leukemia cell expression of Mcl-1, and significantly suppressed HK-induced protection against apoptosis, whereas control oligonucleotides had no effect. Thus, HK cells protect CLL B cells against apoptosis, at least in part through a CD44-dependent mechanism involving up-regulation of Mcl-1, and this mechanism is distinct from that achieved by CD40 ligation. Consequently, the particular antiapoptotic proteins important for CLL survival may vary depending on the microenvironment.
authors.affiliation: The Burnham Institute, La Jolla, CA 92037, USA.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Pedersen
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kitada
authors.forename: Lorenzo M
authors.initials: LM
authors.lastname: Leoni
authors.forename: Juan M
authors.initials: JM
authors.lastname: Zapata
authors.forename: James G
authors.initials: JG
authors.lastname: Karras
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tsukada
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Yong Sung
authors.initials: YS
authors.lastname: Choi
authors.forename: Frank
authors.initials: F
authors.lastname: Bennett
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D017209:Apoptosis / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication; D002470:Cell Survival; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000276:immunology; D019253:Proto-Oncogene Proteins c-bcl-2; D014407:Tumor Cells, Cultured
chemical_list: D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D023201:CD40 Ligand