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• W2051208771 abstract "Small cell lymphocytic lymphoma/chronic lymphocytic leukaemia (SLL/CLL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas, characterized by malignant B cells in bone marrow, secondary lymphoid tissue and blood. The clinical course can vary, and CLL patients with unmutated immunoglobulin heavy chain variable genes (IGHV) have a shorter overall survival (OS) compared to patients with mutated IGHV (Dighiero & Hamblin, 2008). Furthermore, B-cell receptor (BCR) and CD40 signalling are important for the survival and proliferation of normal and malignant B-cells. We recently identified a new lymphoma B cell subset in follicular lymphoma (FL), characterized by impaired BCR signalling, and found that the prevalence of this subset was negatively associated with the response to initial chemotherapy and with OS (Irish et al, 2010). The present study investigated whether a similar lymphoma subset also could be found in SLL/CLL and MZL patients. The study was approved by the Regional Committee for Medical Research Ethics and all specimens were obtained after written informed consent. Patient characteristics are shown in Table 1, and included 11 cases of SLL/CLL and five cases of MZL, all with long-term follow-up. Samples taken prior to treatment and stored as frozen single cell suspensions from tumour biopsies, were thawed, and signalling was induced by activation with CD40 ligand (CD40LG) or BCR cross-linking by F(ab′)2 (anti-BCR), followed by phospho-flow cytometry measurements as previously described (Irish et al, 2010; Data S1). A representative overview of the signalling profiles of lymphoma B cells are presented as histogram overlays of median fluorescence intensity (MFI), relative to unstimulated cells (Fig 1A). In lymphoma cells, CD40LG induced p-S6 and p-p65[nuclear factor (NF)-κB], whereas anti-BCR induced p-S6 and p-PLCγ (Fig 1A). Analysis of the signalling responses across the patient cohort showed large variability in CD40LG-induced p-p65 and p-S6 in lymphoma cells (Fig 1B). We therefore analysed whether CD40LG-induced p-p65/p-S6 was associated with patient OS, and found that patients whose lymphoma cells had higher than median phosphorylation of CD40LG-induced p-p65 and p-S6, had improved OS (Fig. 1C; P = 0·022). p-p65 and p-S6 responses also had prognostic power as single factors (P = 0·022 and P = 0·022, respectively). In FL, we also found that CD40LG-induced p-p65 (NF-κB) correlated with improved OS (Irish et al, 2010). The importance of CD40 signalling for B-CLL cell survival has been described, as autologous B-CLL cells transfected with CD154 (CD40LG) showed enhanced susceptibility to death-receptor-mediated or drug-induced apoptosis (Wierda et al, 2010) and induced anti-leukaemic immune responses (Kato et al, 1998). Next, we examined signalling in lymphoma B cells after BCR activation. Relative MFI for 13 investigated phospho-proteins, including p-Src family kinases (SFKs), p-SYK, p-PLCγ and p-ERK could not stratify patient survival in this cohort. However, as per-cell phospho-flow signalling revealed to be a more powerful predictor in FL (Irish et al, 2010), the per-cell activation of BCR-induced signalling was analysed in SLL/CLL and MZL. Three dimensional (3D) heatmap plots with CD20, BCL2 and phospho-protein expression were generated for this purpose (Fig 1D). The most robust BCR signalling readout in 3D heatmap plots was p-PLCγ, of which most of the patients' had detectable levels in a subpopulation of lymphoma B cells. Lymphoma B cells with no detectable BCR-induced phosphorylation of any of the measured phospho-proteins, including p-PLCγ, p-SFKs, p-SYK/ZAP-70, p-ERK, p-AKT and p-STAT5, were defined as BCR insensitive lymphoma B cells. This subset was calculated in each patient sample as a percentage of the total lymphoma B cells (Fig 1D). Of note, adding the phosphatase inhibitor, H2O2, together with anti-BCR restored signalling also in cases classified as BCR insensitive (Fig S1). Similar to the observations in FL, (Irish et al, 2010) SLL/CLL and MZL lymphoma patients showed a highly variable percentage (5–100%) of BCR-insensitive B lymphoma cells (Fig 1E). Survival analysis showed that patients with more than 60% BCR-insensitive lymphoma cells had a shorter OS, compared to patients with less than 60% BCR-insensitive cells (Fig 1F; P = 0·032). Therefore, this study illustrates a correlation between BCR signalling in lymphoma B cells and patient prognosis. Of note, earlier studies of CLL patients with unusual clinical regression after more than 10 years of follow-up showed that BCR signalling pathway genes are overrepresented in the CLL clones with spontaneous regression (Del Giudice et al, 2009). In CLL patients, a defined side population of leukaemia cells with phenotypic and cytogenetic hallmarks of B-CLL has recently been demonstrated to be chemo-resistant even before therapy (Gross et al, 2010). However, this B-CLL side population was considerably smaller than the subpopulation of BCR-insensitive lymphoma cells demonstrated here. Therefore, whether there is a functional relationship between these two subpopulations of lymphoma B cells will require further investigation. BCR signalling has been associated with unmutated IGHV status in CLL (Lanham et al, 2003; Guarini et al, 2008), in contrast to SLL and MZL where no significant difference in OS between patients with unmutated and mutated IGHV have been reported (Traverse-Glehen et al, 2005; Daudignon et al, 2010). IGHV mutational status did not predict OS in our SLL/MZL patient cohort, nor was it associated with the prevalence of the BCR-insensitive lymphoma subset. Further knowledge regarding BCR signalling and subpopulations of lymphoma cells could guide development of new therapies with the potential to cure indolent lymphoma as this specific subset of BCR-insensitive lymphoma B cells can be identified and tracked during therapy. Flow cytometry-based single-cell analysis has potential for both risk evaluation and surrogate marker assessment in clinical studies because the method is relative fast and enables the analysis of combined lineage markers and signalling processes in individual cells. In summary, our data demonstrate that SLL/CLL and MZL patients, who showed impaired signalling in the majority of their lymphoma B cells after BCR stimulation, had an adverse outcome. Furthermore, the study indicates that patients with high CD40LG-induced p-S6 and p-p65 NF-κB in lymphoma B cells have a significantly better OS. The altered patterns of signalling through BCR and CD40, which has now been shown to predict outcome in FL, SLL/CLL and MZL, may represent a general mechanism for indolent B cell lymphoma, and thus an opportunity for targeted therapies across subtypes of B cell lymphoma. The online version of this article contains a data supplement. E.S.B was supported by grant from Helse Nord. J.H.M was supported by the Norwegian Cancer Society and the Research Council of Norway. The authors thank Ron Levy for supporting this work and reading the manuscript, Tor B. Stuge for technical counselling and Maria Therese Ahlen for isolation of DNA. ESB, JMI, JHM, AH and AK designed study; ESB conducted experiments; ESB, JMI and JHM analysed data, JD validated all patient diagnoses; AT performed IGHV mutation analysis; A.K provided clinical data; ESB drafted the manuscript and all authors participated in discussion of results and approved final manuscript. The authors declare no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W2051208771 title "Altered BCR and CD40 signalling are associated with clinical outcome in small lymphocytic lymphoma/chronic lymphocytic leukaemia and marginal zone lymphoma patients" @default.
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