IL-4 rescues surface IgM expression in chronic lymphocytic leukemia

Guo, Benqi; Zhang, Lu; Chiorazzi, Nicholas; Rothstein, Thomas L.

doi:10.1182/blood-2015-11-682997

Cited by 40 publications

(41 citation statements)

References 54 publications

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“…Interactions of CLL cells with tissue environmental cells will affect levels of functional BCR IgM/D complex (47). We and others have speculated that the higher sIgM might be a consequence of expression enhancement by tissue-derived IL4 (48,49). However, both fractions increased their relative sIgM levels during therapy, suggesting that the reversible downregulation of sIgM due to antigen is a feature of both recent tissue emigrants and of those circulating in the peripheral blood, where the imprint of antigen engagement is still partially evident (18).…”

Section: Discussionmentioning

confidence: 99%

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

Drennan

Chiodin

D’Avola

et al. 2019

Clinical Cancer Research

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Purpose: In chronic lymphocytic leukemia (CLL), disease progression associates with surface IgM (sIgM) levels and signaling capacity. These are variably downmodulated in vivo and recover in vitro, suggesting a reversible influence of tissuelocated antigen. Therapeutic targeting of sIgM function via ibrutinib, an inhibitor of Bruton tyrosine kinase (BTK), causes inhibition and tumor cell redistribution into the blood, with significant clinical benefit. Circulating CLL cells persist in an inhibited state, offering a tool to investigate the effects of drug on BTK-inhibited sIgM.Experimental Design: We investigated the consequences of ibrutinib therapy on levels and function of sIgM in circulating leukemic cells of patients with CLL.Results: At week 1, there was a significant increase of sIgM expression (64% increase from pretherapy) on CLL cells either recently released from tissue or persisting in blood. In contrast, surface IgD (sIgD) and a range of other receptors did not change. SIgM levels remained higher than pretherapy in the following 3 months despite gradual cell size reduction and ongoing autophagy and apoptotic activity. Conversely, IgD and other receptors did not increase and gradually declined. Recovered sIgM was fully N-glycosylated, another feature of escape from antigen, and expression did not increase further during culture in vitro. The sIgM was fully capable of mediating phosphorylation of SYK, which lies upstream of BTK in the Bcell receptor pathway.Conclusions: This specific IgM increase in patients underpins the key role of tissue-based engagement with antigen in CLL, confirms the inhibitory action of ibrutinib, and reveals dynamic adaptability of CLL cells to precision monotherapy. Figure 2.Surface expression of receptors on CLL cells during the first 3 months of ibrutinib therapy. PBMCs were taken at pre-, week 1, month 1, or month 3 of ibrutinib therapy and analyzed for cell surface marker expression taking into account CLL cell size. For each marker, the test MFI was divided by FSC 2 . Pretherapy values were normalized to one (white bar). Each bar represents mean with SEM. The statistical significance of difference was analyzed using the Wilcoxon signed rank test of the FSC-adjusted MFI values. Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P 0.001. Drennan et al.

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Section: Discussionmentioning

confidence: 99%

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

Drennan

Chiodin

D’Avola

et al. 2019

Clinical Cancer Research

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“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Myklebust

Brody

Kohrt

et al. 2017

Blood

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• Contrasting patterns of basal phosphorylation levels and a-BCR-induced signaling between CLL and MCL tumors.• Direct association between BCR-induced signaling strength and CD79B level, but inverse association with BTK and SYK inhibitor efficacy.Kinases downstream of B-cell antigen receptor (BCR) represent attractive targets for therapy in non-Hodgkin lymphoma (NHL). As clinical responses vary, improved knowledge regarding activation and regulation of BCR signaling in individual patients is needed. Here, using phosphospecific flow cytometry to obtain malignant B-cell signaling profiles from 95 patients representing 4 types of NHL revealed a striking contrast between chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) tumors. Lymphoma cells from diffuse large Bcell lymphoma patients had high basal phosphorylation levels of most measured signaling nodes, whereas follicular lymphoma cells represented the opposite pattern with no or very low basal levels. MCL showed large interpatient variability in basal levels, and elevated levels for the phosphorylated forms of AKT, extracellular signal-regulated kinase, p38, STAT1, and STAT5 were associated with poor outcome. CLL tumors had elevated basal levels for the phosphorylated forms of BCR-signaling nodes (Src family tyrosine kinase, spleen tyrosine kinase [SYK], phospholipase Cg), but had low a-BCR-induced signaling. This contrasted MCL tumors, where a-BCR-induced signaling was variable, but significantly potentiated as compared with the other types. Overexpression of CD79B, combined with a gating strategy whereby signaling output was directly quantified per cell as a function of CD79B levels, confirmed a direct relationship between surface CD79B, immunoglobulin M (IgM), and IgM-induced signaling levels. Furthermore, a-BCR-induced signaling strength was variable across patient samples and correlated with BCR subunit CD79B expression, but was inversely correlated with susceptibility to Bruton tyrosine kinase (BTK) and SYK inhibitors in MCL. These individual differences in BCR levels and signaling might relate to differences in therapy responses to BCR-pathway inhibitors. (Blood. 2017;129(6):759-770)

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“…This finding is particularly relevant because IL-4 regulation of B-cell receptor signaling has been identified as integral to CLL (in CLL, both B-and T-cells highly express IL-4). [60][61][62] We then performed a secondary analysis to identify KEGG pathways using BinoX 63 and noted thyroid hormone signaling, notch signaling, viral carcinogenesis and, interestingly, chronic myeloid leukemia.…”

Section: Sf3b1mentioning

confidence: 99%

Genomic data integration in chronic lymphocytic leukemia

Fernández-Martínez

deAndrés-Galiana

Sonis³

2017

The Journal of Gene Medicine

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IL-4 rescues surface IgM expression in chronic lymphocytic leukemia

Abstract: Key Points Low level of total CD79b protein impairs BCR assembly in CLL samples. IL-4 rescues CD79b protein and sIgM and BCR signaling in CLL samples.

Cited by 40 publications

References 54 publications

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

Ibrutinib Therapy Releases Leukemic Surface IgM from Antigen Drive in Chronic Lymphocytic Leukemia Patients

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

Genomic data integration in chronic lymphocytic leukemia

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