title: IL-4 enhances expression and function of surface IgM in CLL cells.
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.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Maria M
authors.initials: MM
authors.lastname: Aguilar-Hernandez
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Blunt
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Rachel
authors.initials: R
authors.lastname: Dobson
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Alison
authors.initials: A
authors.lastname: Yeomans
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Stephen
authors.initials: S
authors.lastname: Thirdborough
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Marta
authors.initials: M
authors.lastname: Larrayoz
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Lindsay D
authors.initials: LD
authors.lastname: Smith
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Adam
authors.initials: A
authors.lastname: Linley
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
authors.affiliation: Medical Oncology, University Hospital Southampton National Health Service Trust, Southampton, United Kingdom;
authors.forename: Andrew
authors.initials: A
authors.lastname: Davies
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Medical Oncology, University Hospital Southampton National Health Service Trust, Southampton, United Kingdom;
authors.forename: Peter M W
authors.initials: PM
authors.lastname: Johnson
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Natalia
authors.initials: N
authors.lastname: Savelyeva
authors.affiliation: Antibody and Vaccine Group, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; and.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Cragg
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom; Haematology Department, University Hospital Southampton National Health Service Trust, Southampton, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Graham
authors.initials: G
authors.lastname: Packham
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Freda K
authors.initials: FK
authors.lastname: Stevenson
authors.affiliation: Cancer Research UK Centre, Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom;
authors.forename: Andrew J
authors.identifier: 0000-0003-0667-1596
authors.initials: AJ
authors.lastname: Steele
mesh_terms: D002462:Cell Membrane / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004347:Drug Interactions; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics* / Q000378:metabolism*; D015847:Interleukin-4 / Q000494:pharmacology*; D053616:Janus Kinase 3 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000276:immunology / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C508598:IL4 protein, human; D007075:Immunoglobulin M; D047428:Protein Kinase Inhibitors; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; D015847:Interleukin-4; D011505:Protein-Tyrosine Kinases; D053616:Janus Kinase 3