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PLoS One. 2014 Oct 3;9(10):e109533. doi: 10.1371/journal.pone.0109533. eCollection 2014.

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.

Author information

1
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.
2
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.
3
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.
4
Servicio de Hematología y Hemoterapia, Hospital General Universitario Santa Lucía, Cartagena, Spain.
5
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.

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.

PMID:
25280001
PMCID:
PMC4184842
DOI:
10.1371/journal.pone.0109533
[Indexed for MEDLINE]
Free PMC Article
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