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Toll-like receptor 9 stimulation can induce I?B? expression and IgM secretion in chronic lymphocytic leukemia cells.

ABSTRACT: 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 I?B? protein in a selected group of cases, through an unanticipated post-transcriptional mechanism. Interestingly, I?B? plays a causal role in sustaining CpG-induced cell viability and chemoresistance, and CpG stimulation can unleash immunoglobulin secretion by I?B?-positive malignant cells. These results identify and characterize I?B? as a marker and effector molecule of distinct key pathways in chronic lymphocytic leukemia.

SUBMITTER: Fonte E

PROVIDER: S-EPMC5664394 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Toll-like receptor 9 stimulation can induce IκBζ expression and IgM secretion in chronic lymphocytic leukemia cells.

Fonte Eleonora E Vilia Maria Giovanna MG Reverberi Daniele D Sana Ilenia I Scarfò Lydia L Ranghetti Pamela P Orfanelli Ugo U Cenci Simone S Cutrona Giovanna G Ghia Paolo P Muzio Marta M

Haematologica 20170803 11

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 undef ...[more]

PMID: 28775123

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Project description:Chronic lymphocytic leukemia (CLL) usually involves the expansion of a clone of CD5+ B cells synthesizing IgM antibodies. These B cells appear to be blocked at the antigen receptor-expressing stage of B cell differentiation and are thought not to undergo an isotype class switch to IgG or IgA production. In vivo and in vitro studies suggest, however, that in some instances terminal differentiation and isotype switching can occur. To test the hypothesis that in vivo isotype class switching occurs in IgM+ B-type CLL cells, we analyzed the PBMC of 19 CLL patients for the presence of transcripts encoding the rearranged CLL V(H)DJ(H) associated with either gamma or alpha H chains. The molecular data indicate that approximately 50% of B-CLL patients have amplifications of IgM+ B cells that undergo an isotype class switch. Switching to IgA appears to occur more often than to IgG; also, switching can involve different IgG subclasses in individual patients. In many instances, these CLL-related gamma and alpha transcripts are much more plentiful than those of normal B cells that produce the same isotype. These switched transcripts do not reveal evidence for the accumulation of significant numbers of new V(H) gene mutations. The cellular data indicate that B cells with lesser amounts of surface membrane IgD and higher IgM/IgD ratios are more likely to undergo this switching process. Furthermore, B cells expressing IgG and IgA of the same idiotype or V(H) family and the same CDR3 length as those of the CLL IgM+ clone can be identified in the blood of patients studied using multiparameter immunofluorescence analyses. Collectively, these data suggest that not all members of a B-CLL clone are frozen at the surface membrane Ig-expressing stage of B cell maturation, and that some members can switch to the production of non-IgM isotypes. The occurrence of switching without the accumulation of V gene mutations indicates that the processes of differentiation and diversification are not linked.

Dataset Information

Toll-like receptor 9 stimulation can induce I?B? expression and IgM secretion in chronic lymphocytic leukemia cells.

Publications

Toll-like receptor 9 stimulation can induce IκBζ expression and IgM secretion in chronic lymphocytic leukemia cells.

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