TY - JOUR
T1 - Toll-like receptor 9 stimulation can induce IκBζ expression and IgM secretion in chronic lymphocytic leukemia cells
AU - Fonte, E
AU - Vilia, MG
AU - Reverberi, D
AU - Sana, I
AU - Scarfò, L
AU - Ranghetti, P
AU - Orfanelli, U
AU - Cenci, S
AU - Cutrona, G
AU - Ghia, P
AU - Muzio, M
PY - 2017
Y1 - 2017
N2 - Chronic lymphocytic leukemia cells strongly depend on external stimuli for their survival. Both antigen receptor and co-stimulatory receptors, including Toll-like receptors, can modulate viability and proliferation of leukemic cells. Toll-like receptor ligands, and particularly the TLR9 ligand CpG, mediate heterogeneous responses in patients’ samples reflecting the clinical course of the subjects. However, the molecular framework of the key signaling events underlying such heterogeneity is undefined. We focused our studies on a subset of chronic lymphocytic leukemia cases characterized by expression of CD38 and unmutated immunoglobulin genes, who respond to CpG with enhanced metabolic cell activity. We report that, while CpG induces NFKBIZ mRNA in all the samples analyzed, it induces the IκBζ protein in a selected group of cases, through an unanticipated post-transcriptional mechanism. Interestingly, IκBζ plays a causal role in sustaining CpG-induced cell viability and chemoresistance, and CpG stimulation can unleash immunoglobulin secretion by IκBζ-positive malignant cells. These results identify and characterize IκBζ as a marker and effector molecule of distinct key pathways in chronic lymphocytic leukemia. © 2017 Ferrata Storti Foundation.
AB - Chronic lymphocytic leukemia cells strongly depend on external stimuli for their survival. Both antigen receptor and co-stimulatory receptors, including Toll-like receptors, can modulate viability and proliferation of leukemic cells. Toll-like receptor ligands, and particularly the TLR9 ligand CpG, mediate heterogeneous responses in patients’ samples reflecting the clinical course of the subjects. However, the molecular framework of the key signaling events underlying such heterogeneity is undefined. We focused our studies on a subset of chronic lymphocytic leukemia cases characterized by expression of CD38 and unmutated immunoglobulin genes, who respond to CpG with enhanced metabolic cell activity. We report that, while CpG induces NFKBIZ mRNA in all the samples analyzed, it induces the IκBζ protein in a selected group of cases, through an unanticipated post-transcriptional mechanism. Interestingly, IκBζ plays a causal role in sustaining CpG-induced cell viability and chemoresistance, and CpG stimulation can unleash immunoglobulin secretion by IκBζ-positive malignant cells. These results identify and characterize IκBζ as a marker and effector molecule of distinct key pathways in chronic lymphocytic leukemia. © 2017 Ferrata Storti Foundation.
U2 - 10.3324/haematol.2017.165878
DO - 10.3324/haematol.2017.165878
M3 - Article
VL - 102
SP - 1901
EP - 1912
JO - Haematologica
JF - Haematologica
SN - 0390-6078
IS - 11
ER -