title: The gene expression response of chronic lymphocytic leukemia cells to IL-4 is specific, depends on ZAP-70 status and is differentially affected by an NFκB inhibitor.
abstract: Interleukin 4 (IL-4), an essential mediator of B cell development, plays a role in survival of chronic lymphocytic leukemia (CLL) cells. To obtain new insights into the function of the IL-4 pathway in CLL, we analyzed the gene expression response to IL-4 in CLL and in normal B cells (NBC) by oligonucleotide microarrays, resulting in the identification of 232 non-redundant entities in CLL and 146 in NBC (95 common, 283 altogether), of which 189 were well-defined genes in CLL and 123 in NBC (83 common, 229 altogether) (p<0.05, 2-fold cut-off). To the best of our knowledge, most of them were novel IL-4 targets for CLL (98%), B cells of any source (83%), or any cell type (70%). Responses were significantly higher for 54 and 11 genes in CLL and NBC compared to each other, respectively. In CLL, ZAP-70 status had an impact on IL-4 response, since different sets of IL-4 targets correlated positively or negatively with baseline expression of ZAP-70. In addition, the NFκB inhibitor 6-Amino-4-(4-phenoxyphenethylamino)quinazoline, which reversed the anti-apoptotic effect of IL-4, preferentially blocked the response of genes positively correlated with ZAP-70 (e.g. CCR2, SUSD2), but enhanced the response of genes negatively correlated with ZAP-70 (e.g. AUH, BCL6, LY75, NFIL3). Dissection of the gene expression response to IL-4 in CLL and NBC contributes to the understanding of the anti-apoptotic response. Initial evidence of a connection between ZAP-70 and NFκB supports further exploration of targeting NFκB in the context of the assessment of inhibition of the IL-4 pathway as a therapeutic strategy in CLL, especially in patients expressing bad prognostic markers.
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ruiz-Lafuente
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: María-José
authors.initials: MJ
authors.lastname: Alcaraz-García
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sebastián-Ruiz
authors.affiliation: Servicio de Hematología y Hemoterapia, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Joaquín
authors.initials: J
authors.lastname: Gómez-Espuch
authors.affiliation: Servicio de Hematología y Hemoterapia, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Funes
authors.affiliation: Servicio de Hematología y Hemoterapia, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Universidad de Murcia, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: José-María
authors.initials: JM
authors.lastname: Moraleda
authors.affiliation: Servicio de Hematología y Hemoterapia, Hospital General Universitario Santa Lucía, Cartagena, Spain.
authors.forename: María-Carmen
authors.initials: MC
authors.lastname: García-Garay
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Natividad
authors.initials: N
authors.lastname: Montes-Barqueros
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Minguela
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Centro de Investigación Biomédica en Red de enfermedades hepáticas y digestivas, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: María-Rocío
authors.initials: MR
authors.lastname: Álvarez-López
authors.affiliation: Servicio de Inmunología, Hospital Clínico Universitario Virgen de la Arrixaca, Murcia, Spain; Instituto Murciano de Investigación Biosanitaria Virgen de la Arrixaca (IMIB-Arrixaca), Murcia, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Parrado
mesh_terms: D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics*; D015153:Blotting, Western; D016022:Case-Control Studies; D049109:Cell Proliferation; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics*; D015847:Interleukin-4 / Q000494:pharmacology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D020672:I-kappa B Proteins; C508598:IL4 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D015847:Interleukin-4; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human