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IL-4 enhances expression and function of surface IgM in CLL cells

Maria M. Aguilar-Hernandez, Matthew D. Blunt, Rachel Dobson, Alison Yeomans, Stephen Thirdborough, Marta Larrayoz, Lindsay D. Smith, Adam Linley, Jonathan C. Strefford, Andrew Davies, Peter M.W. Johnson, Natalia Savelyeva, Mark Cragg, Francesco Forconi, Graham Packham, Freda K. Stevenson and Andrew J. Steele

Key points

  • 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 BTK or PI3K inhibitors on sIgM-mediated signalling.

Abstract

Kinase-inhibitors targeting the B-cell receptor (BCR) are now prominent in the treatment of CLL. We have focused here on IL-4, a cytokine which protects normal and malignant B cells from apoptosis, and increases surface (s)IgM 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 to 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 (U-CLL). IL-4-induced sIgM expression was associated with increased receptor signalling activity, measured by anti-IgM-induced calcium mobilisation, and with increased expression of CD79B mRNA 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 pre-treatment 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 U-CLL 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.

  • Submitted November 30, 2015.
  • Accepted March 16, 2016.