Integration of innate into adaptive immune responses in ZAP-70–positive chronic lymphocytic leukemia

Wagner, Michaela; Oelsner, Madlen; Moore, Andrew R.; Götte, Frederik; Kuhn, Peer‐Hendrik; Haferlach, Torsten; Fiegl, Michael; Bogner, Christian; Baxter, E. Joanna; Peschel, Christian; Follows, George; Ringshausen, Ingo

doi:10.1182/blood-2015-05-646935

Cited by 26 publications

(25 citation statements)

References 38 publications

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“…recently described a signaling framework that links TLR9 activation, in ZAP70-positive CLL, with protection from apoptosis mediated by IgM secretion. 40 Our results support and extend this observation, and suggest that TLR9-induced IgM secretion and metabolic cell activation in IκBζ-positive cases may play a key role in tuning CLL cell survival.…”

Section: Discussionsupporting

confidence: 86%

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

et al. 2017

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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.

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Section: Discussionsupporting

confidence: 86%

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

et al. 2017

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“…reported that ZAP70 − /immunoglobulin variable region heavy chain (IGVH) gene mutated CLL cells become apoptotic in response to CpG-ODN, in contrast to ZAP70 + /IGVH unmutated, which respond proliferatively 65 . However, other studies found lack of activation/proliferation of CLL/MCL cells with CpG-ODN 66–69 .…”

Section: 0 Discussionmentioning

confidence: 99%

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

Jayappa

Portell²,

Gordon

et al. 2017

Blood Advances

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De novo resistance and rapid recurrence often characterize responses of B-cell malignancies to ibrutinib (IBR), indicating a need to develop drug combinations that block compensatory survival signaling and give deeper, more durable responses. To identify such combinations, we previously performed a combinatorial drug screen and identified the Bcl-2 inhibitor venetoclax (VEN) as a promising partner for combination with IBR in Mantle Cell Lymphoma (MCL). We have opened a multi-institutional clinical trial to test this combination. However, analysis of primary samples from patients with MCL as well as chronic lymphocytic leukemia (CLL) revealed unexpected heterogeneous de novo resistance even to the IBR+VEN combination. In the current study, we demonstrate that resistance to the combination can be generated by microenvironmental agonists: IL-10, CD40L and, most potently, CpG-oligodeoxynucleotides (CpG-ODN), which is a surrogate for unmethylated DNA and a specific agonist for TLR9 signaling. Incubation with these agonists caused robust activation of NF-κB signaling, especially alternative NF-κB, which led to enhanced expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, and survivin, thus decreasing dependence on Bcl-2. Inhibitors of NF-κB signaling blocked overexpression of these anti-apoptotic proteins and overcame resistance. Inhibitors of Mcl-1, Bcl-xL, or survivin also overcame this resistance, and showed synergistic benefit with the IBR+VEN combination. We conclude that microenvironmental factors, particularly the TLR9 agonist, can generate de novo resistance to the IBR+VEN combination in CLL and MCL cells. This signaling pathway presents targets for overcoming drug resistance induced by extrinsic microenvironmental factors in diverse B-cell malignancies.

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“…TLR2 is the receptor responsible for recognizing the bacterial cell wall components such as lipoproteins, peptidoglycan, lipoteichoic acid. Recent studies suggest that disorders of TLRs’ expression may be important in the development of CLL (Ntoufa et al 2016; Wagner et al 2016), though the mechanism underlying the development of the disease still remains unexplained. We found significantly lower percentage of CD19 + /CD5 + TLR2 + cells in patients with CLL comparing to the control group that is in line with the data obtained by Grandjenette et al (2007) and Muzio et al (2008) who demonstrated lower expression of TLRs on leukemia cells as compared to normal B cells.…”

Section: Discussionmentioning

confidence: 99%

TLR2 Expression on Leukemic B Cells from Patients with Chronic Lymphocytic Leukemia

Szymańska

Bojarska‐Junak

Drobiecki

et al. 2018

Arch. Immunol. Ther. Exp.

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Antigenic stimulation is considered as a possible trigger of neoplastic transformation in chronic lymphocytic leukemia (CLL). B-cell receptor plays a key role in the interactions between the microenvironment and leukemic cells; however, an important role has also been attributed to Toll-like receptors (TLRs). It is believed that disorders of TLR expression may play a part in the pathogenesis of CLL. In this study, we investigated the potential role of TLR2 in CLL by analyzing its expression on leukemic B cells in correlation with clinical and laboratory parameters characterizing disease activity and patients' immune status. We assessed the frequencies of TLR2/CD19 cells by the flow cytometry method in peripheral blood of 119 patients with CLL. The percentage of TLR2/CD19 cells was significantly lower in patients with CLL as compared to the healthy volunteers. There was also a lower percentage of TLR2/CD19 cells in CLL patients with poor prognostic factors, such as ZAP70 and/or CD38 expression, 17p and/or 11q deletion. On the other hand, among patients with del(13q14) associated with favorable prognosis, the percentage of TLR2/CD19 cells was higher than among those with del(11q22) and/or del(17p13) as well as in the control group. We found an association between low percentage of CD19/CD5/TLR2 cells and shorter time to treatment. We also demonstrated the relationship between low percentage of CD19/CD5 TLR2-positive and overall survival (OS) of CLL patients. CLL patients with a proportion of 1.6% TLR2-positive B CD5 cells (according to the receiver operating characteristic curve analysis) or more had a longer time to treatment and longer OS than the group with a lower percentage of TLR2 positive cells. To sum up, the results of the study suggest that low TLR2 expression is associated with poor prognosis in CLL patients. The monitoring of CD19/CD5/TLR2 cells number may provide useful information on disease activity. Level of TLR2 expression on leukemic B cells may be an important factor of immunological dysfunction for patients with CLL. Our study suggests that TLR2 could becomes potential biological markers for the clinical outcome in patients with CLL.

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Integration of innate into adaptive immune responses in ZAP-70–positive chronic lymphocytic leukemia

Cited by 26 publications

References 38 publications

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

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

Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL

TLR2 Expression on Leukemic B Cells from Patients with Chronic Lymphocytic Leukemia

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