title: Chronic lymphocytic leukemia cells display p53-dependent drug-induced Puma upregulation.
abstract: We investigated the apoptosis gene expression profile of chronic lymphocytic leukemia (CLL) cells in relation to (1) normal peripheral and tonsillar B-cell subsets, (2) IgV(H) mutation status, and (3) effects of cytotoxic drugs. In accord with their noncycling, antiapoptotic status in vivo, CLL cells displayed high constitutive expression of Bcl-2 and Flip mRNA, while Survivin, Bid and Bik were absent. Paradoxically, along with these antiapoptotic genes CLL cells had high-level expression of proapoptotic BH3-only proteins Bmf and Noxa. Treatment of CLL cells with fludarabine induced only the proapoptotic genes Bax and Puma in a p53-dependent manner. Interestingly, the degree of Puma induction was more pronounced in cells with mutated IgVH genes. Thus, disturbed apoptosis in CLL is the net result of both protective and sensitizing aberrations. This delicate balance can be tipped via induction of Puma in a p53-dependent matter, the level of which may vary between groups of patients with a different tendency for disease progression.
authors.affiliation: Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: W J M
authors.initials: WJ
authors.lastname: Mackus
authors.forename: A P
authors.initials: AP
authors.lastname: Kater
authors.forename: A
authors.initials: A
authors.lastname: Grummels
authors.forename: L M
authors.initials: LM
authors.lastname: Evers
authors.forename: B
authors.initials: B
authors.lastname: Hooijbrink
authors.forename: M H H
authors.initials: MH
authors.lastname: Kramer
authors.forename: J E
authors.initials: JE
authors.lastname: Castro
authors.forename: T J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: R A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: M H J
authors.initials: MH
authors.lastname: van Oers
authors.forename: E
authors.initials: E
authors.lastname: Eldering
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling / Q000379:methods; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D001084:Vidarabine Phosphate; C042382:fludarabine phosphate