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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Biomarkers, Tumor / genetics*
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Blotting, Western
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Case-Control Studies
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Cell Proliferation
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Cells, Cultured
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Gene Expression Profiling*
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Humans
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I-kappa B Proteins / genetics*
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Interleukin-4 / pharmacology*
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Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
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Leukemia, Lymphocytic, Chronic, B-Cell / pathology
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Lymphocytes / cytology
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Lymphocytes / metabolism
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NF-kappa B / antagonists & inhibitors*
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NF-kappa B / genetics
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Oligonucleotide Array Sequence Analysis
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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ZAP-70 Protein-Tyrosine Kinase / genetics*
Substances
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Biomarkers, Tumor
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I-kappa B Proteins
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IL4 protein, human
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NF-kappa B
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RNA, Messenger
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Interleukin-4
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ZAP-70 Protein-Tyrosine Kinase
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ZAP70 protein, human
Grants and funding
This work was supported by grants from Plan Nacional de I+D+I 2004-2007, Programa de Promoción de la Investigación Biomédica y en Ciencias de la Salud del Ministerio de Sanidad y Consumo (PI07/0135 to AP) and Plan Nacional de I+D+I 2008-2011, Acción Estratégica en Salud (PI10/01226 to AP) (Instituto de Salud Carlos III (ISCIII) co-financed with European Regional Development Funds, “Una manera de hacer Europa”), II PCTRM 2007–2010, Fundación Séneca, Agencia de Ciencia y Tecnología de la Región de Murcia (08721/PI/08 to AP, and 04487/GERM/06 to MRAL), ISCIII Spanish Cell Therapy Network (Tercel; RD06/0010/0023 to JMM), and the CIBERehd scientific program to MRAL. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.