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

Blood. 2016 Jun 16;127(24):3015-25. doi: 10.1182/blood-2015-11-682906. Epub 2016 Mar 21.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Membrane / metabolism*
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Cells, Cultured
  • Drug Interactions
  • Gene Expression Regulation, Leukemic / drug effects
  • Humans
  • Immunoglobulin M / genetics*
  • Immunoglobulin M / metabolism*
  • Interleukin-4 / pharmacology*
  • Janus Kinase 3 / metabolism
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Neutrophils / drug effects
  • Neutrophils / metabolism
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • STAT6 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Up-Regulation / drug effects


  • IL4 protein, human
  • Immunoglobulin M
  • Protein Kinase Inhibitors
  • STAT6 Transcription Factor
  • STAT6 protein, human
  • Interleukin-4
  • Protein-Tyrosine Kinases
  • Janus Kinase 3