title: CD154 induces a switch in pro-survival Bcl-2 family members in chronic lymphocytic leukaemia.
abstract: Chronic lymphocytic leukaemia cells survive and proliferate in patients but rapidly die in culture. The microenvironment that sustains leukaemic cells in vivo contains both stromal cell elements and T cells. We defined changes in Bcl-2 family protein expression on culture with CD40 ligand (CD154) expressed on mouse fibroblast L cells, and interleukin-4 (IL-4; CD154/IL-4 system): conditions that support survival and proliferation. Unexpectedly, Bcl-2 protein expression decreased whilst pro-survival Bcl-x(L) (as well as A1 and Mcl-1) increased. However, the CD154-L cell/IL-4 system also increased the pro-apoptotic proteins, Bid and Noxa, suggesting that an increased pool of pro-survival factors and not the effects of a single protein mediate survival. Most pro-apoptotic proteins were not induced in drug or spontaneous apoptosis, but expression of Bcl-x(S), a pro-apoptotic BCL2L1 isoform, was associated with cell death. This was post-transcriptionally controlled, and, therefore, alternative splicing at the Bcl-x locus appears to have a role in the regulation of chronic lymphocytic leukaemia (CLL) cell survival. This study demonstrated a switch in pro-survival proteins associated with the transition from quiescence to CD154-driven proliferation. CLL therapies targeting Bcl-2 may need to be modified to antagonize proliferation centre-specific pro-survival proteins.
authors.affiliation: Division of Investigative Sciences, Department of Haematology, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: Shaun
authors.initials: S
authors.lastname: Willimott
authors.forename: Maria
authors.initials: M
authors.lastname: Baou
authors.forename: Kikkeri
authors.initials: K
authors.lastname: Naresh
authors.forename: Simon D
authors.initials: SD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000032:analysis / Q000378:metabolism; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D015153:Blotting, Western; D023201:CD40 Ligand / Q000494:pharmacology*; D049109:Cell Proliferation; D002470:Cell Survival; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D015847:Interleukin-4 / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D008198:Lymph Nodes / Q000737:chemistry; D051379:Mice; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000032:analysis / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019311:Staurosporine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology; D051020:bcl-X Protein / Q000032:analysis / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C096816:BCL2-related protein A1; C494811:BCL2L1 protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C579094:Mcl1 protein, mouse; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D023201:CD40 Ligand; D015847:Interleukin-4; D011493:Protein Kinase C; D014740:Vidarabine; D019311:Staurosporine; C024352:fludarabine