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Aguilar-Hernandez, Maria M.; Blunt, Matthew D.; Dobson, Rachel; Yeomans, Alison; Thirdborough, Stephen; Larrayoz, Marta; Smith, Lindsay D.; Linley, Adam; Strefford, Jonathan C.; Davies, Andrew; Johnson, Peter M.W.; Savelyeva, Natalia; Cragg, Mark S.; Forconi, Francesco; Packham, Graham; Stevenson, Freda K.; Steele, Andrew J.
Blood, 06/2016, Letnik: 127, Številka: 24Journal Article
Kinase inhibitors targeting the B-cell receptor (BCR) are now prominent in the treatment of chronic lymphocytic leukemia (CLL). We have focused here on interleukin 4 (IL-4), a cytokine that protects normal and malignant B cells from apoptosis and increases surface immunoglobulin M (sIgM) expression on murine splenic B cells. First, we have demonstrated that IL-4 treatment increased sIgM expression in vitro on peripheral blood B cells obtained from healthy individuals. In CLL, IL-4 target genes are overexpressed in cells purified from the lymph nodes of patients compared with cells derived from matched blood and bone marrow samples. As for normal B cells, IL-4 increased sIgM expression on CLL cells in vitro, especially in samples expressing unmutated V-genes. IL-4–induced sIgM expression was associated with increased receptor signalling activity, measured by anti-IgM–induced calcium mobilization, and with increased expression of CD79B messenger RNA and protein, and the “mature” glycoform of sIgM. Importantly, the ability of the BCR-associated kinase inhibitors idelalisib and ibrutinib, approved for treatment of CLL and other B-cell malignancies, to inhibit anti-IgM–induced signalling was reduced following IL-4 pretreatment in samples from the majority of patients. In contrast to stimulatory effects on sIgM, IL-4 decreased CXCR4 and CXCR5 expression; therefore, CLL cells, particularly within the progressive unmutated V-gene subset, may harness the ability of IL-4 to promote BCR signalling and B-cell retention within lymph nodes. Effects of IL-4 were mediated via JAK3/STAT6 and we propose a potential role for JAK inhibitors in combination with BCR kinase inhibitors for the treatment of CLL. •IL-4 treatment augments sIgM expression and subsequent downstream signalling in a JAK3/STAT6 dependent manner within CLL samples.•IL-4 exposure partially opposes the activity of Bruton tyrosine kinase or PI3K inhibitors on sIgM-mediated signalling.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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