IL-4 enhances expression and function of surface IgM in CLL cells. Academic Article uri icon

Overview

abstract

  • 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.

authors

  • Aguilar Hernandez, Maria Montserrat
  • 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

publication date

  • March 21, 2016

Research

keywords

  • Cell Membrane
  • Immunoglobulin M
  • Interleukin-4
  • Leukemia, Lymphocytic, Chronic, B-Cell

Identity

Scopus Document Identifier

  • 84976274450

Digital Object Identifier (DOI)

  • 10.1182/blood-2015-11-682906

PubMed ID

  • 27002119

Additional Document Info

volume

  • 127

issue

  • 24