title: Autocrine interleukin-1beta production in leukemia: evidence for the involvement of mutated RAS.
abstract: Interleukin (IL)-1beta is constitutively expressed in many leukemias and operates as an autocrine growth factor. To study the cellular basis for this aberrant production, we analyzed two cell lines, B1 (acute lymphoblastic leukemia) and W1 (juvenile chronic myelogenous leukemia), which express high levels of IL-1beta and have mutations in the K-RAS and N-RAS genes, respectively. Electromobility shift assays demonstrated transcription factor binding at multiple IL-1beta promoter elements [nuclear factor (NF)-IL6/CREB, NFB1, NFkappaB, and NF-IL6], consistent with the activation of an upstream signaling pathway. To determine whether activated Ras was involved, two structurally distinct classes of farnesyltransferase (FTase) inhibitors (the monoterpenes and a peptidomimetic) and an adenoviral vector expressing antisense targeted to K-RAS were used to specifically interfere with Ras function and/or expression. Treatment with the FTase inhibitors resulted in a concentration-dependent decrease in both NF-IL6/CREB binding to the IL-1beta promoter and IL-1beta protein levels, without a significant change in total cellular protein levels. Furthermore, exposure of the B1 cells to antisense against K-RAS resulted in an approximately 50% reduction in both p21Ras and IL-1beta protein levels. Growth suppression was observed after FTase inhibitor or antisense exposure, an effect that was partially reversible by the addition of recombinant IL-1beta to the cultures. Our observations suggest that mutated RAS genes may mediate autocrine IL-1beta production in some leukemias by stimulating signal transduction pathways that activate the IL-1beta promoter.
authors.affiliation: Department of Bioimmunotherapy, University of Texas M.D. Anderson Cancer Center, Houston 77030, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Beaupre
authors.forename: M
authors.initials: M
authors.lastname: Talpaz
authors.forename: F C
authors.initials: FC
authors.lastname: Marini
authors.forename: R J
authors.initials: RJ
authors.lastname: Cristiano
authors.forename: J A
authors.initials: JA
authors.lastname: Roth
authors.forename: Z
authors.initials: Z
authors.lastname: Estrov
authors.forename: M
authors.initials: M
authors.lastname: Albitar
authors.forename: M H
authors.initials: MH
authors.lastname: Freedman
authors.forename: R
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D019898:Autocrine Communication; D015139:Blotting, Southern; D022762:CCAAT-Enhancer-Binding Proteins; D002455:Cell Division / Q000187:drug effects; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051231:Farnesyltranstransferase; D005784:Gene Amplification; D015870:Gene Expression / Q000187:drug effects; D015321:Gene Rearrangement; D011905:Genes, ras / Q000502:physiology; D006801:Humans; D007223:Infant; D007375:Interleukin-1 / Q000096:biosynthesis* / Q000235:genetics; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger; D015398:Signal Transduction; D013729:Terpenes / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D000893:Anti-Inflammatory Agents; D022762:CCAAT-Enhancer-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007375:Interleukin-1; D009687:Nuclear Proteins; D016376:Oligonucleotides, Antisense; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D013729:Terpenes; D014157:Transcription Factors; D003907:Dexamethasone; D003513:Cycloheximide; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase