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

Abstract

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 Bruton tyrosine kinase or PI3K inhibitors on sIgM-mediated signalling.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. (Blood. 2016;127(24):3015-3025)

Distinct patterns of B-cell receptor signaling in non-Hodgkin lymphomas identified by single-cell profiling

“…53,54 However, CD79B surface expression in CLL is commonly downregulated, 55,56 but can be upregulated upon IL-4 signaling. 57,58 The overall higher surface expression of CD79B in MCL, but not in CLL, suggests it may be a better target for therapy in MCL. Indeed, a recent clinical trial using anti-CD79B antibody conjugate as a single agent or combined with rituximab had no clinical effect in CLL, but had an objective response in 14 of 24 DLBCL patients, and 6 of 7 patients with MCL.…”

IL-4/CXCL12 loop is a key regulator of lymphoid stroma function in follicular lymphoma

“…59 This finding may have important clinical relevance in FL in which immune-checkpoint blockade emerges as a valuable therapeutic approach. Finally, the use of JAK3 or STAT6 inhibitors (recently tested on CLL B cells 60 ) may override the effect of IL-4 on the induction of CXCL12 expression by stromal cells and also on the activation of malignant B cells, especially in combination with inhibition of the BCR signaling pathway 61 and would thus be of potential relevance in FL patients. For personal use only.…”

The Dual Syk/JAK Inhibitor Cerdulatinib Antagonizes B-cell Receptor and Microenvironmental Signaling in Chronic Lymphocytic Leukemia

“…Recently approved agents for relapsed/refractory CLL include ibrutinib (BTK inhibitor) and idelalisib (PI3Kδ inhibitor)(5, 6). To date these compounds have not proved curative, which may in part be due to protection of the tumour by the microenvironment(7). Importantly, a proportion of patients are developing resistance to these new agents.…”

“…Using gene set enrichment analysis we recently identified an IL-4 gene signature which was enriched in lymph node tissue compared with matched blood and bone marrow(7). IL-4 signals in lymphocytes predominantly through the type 1 IL-4 receptor (IL-4R) via Janus protein tyrosine kinases JAK1 and JAK3 resulting in phosphorylation of STAT6 (pSTAT6)(15).…”