Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma

Saba, Nakhle S.; Liu, Delong; Herman, Sarah E. M.; Underbayev, Chingiz; Tian, Xin; Behrend, David; Weniger, Marc A.; Skarzynski, Martin; Gyamfi, Jennifer; Fontán, Lorena; Melnick, Ari; Grant, Clíona; Roschewski, Mark; Navarro, Alba; Beà, Sı́lvia; Pittaluga, Stefania; Dunleavy, Kieron; Wilson, Wyndham H.; Wiestner, Adrian

doi:10.1182/blood-2015-11-681460

Cited by 133 publications

(159 citation statements)

References 46 publications

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“…To that end we adapted a published algorithm (Houseman et al, 2012; Jaffe and Irizarry, 2014) to estimate the fractions of 6 different hematopoietic cell types (Reinius et al, 2012) in our tumor samples (Figure 1B). The normal B cell fraction in MCL samples is estimated to be very low (0-0.3%) (Saba et al, 2016), therefore the total B cell fraction was taken as a measure for the tumor fraction. Using the adapted algorithm, we calculated the proportion of each cell type in our samples.…”

Section: Resultsmentioning

confidence: 99%

Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

et al. 2016

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Summary We analyzed the in silico purified DNA methylation signatures of 82 mantle cell lymphomas (MCL) in comparison with cell subpopulations spanning the entire B cell lineage. We identified two MCL subgroups, respectively carrying epigenetic imprints of germinal center-inexperienced and germinal center-experienced B cells, and we found that DNA methylation profiles during lymphomagenesis are largely influenced by the methylation dynamics in normal B cells. An integrative epigenomic approach revealed 10,504 differentially methylated regions in regulatory elements marked by H3K27ac in MCL primary cases, including a distant enhancer showing de novo looping to the MCL oncogene SOX11. Finally, we observed that the magnitude of DNA methylation changes per case is highly variable and serves as an independent prognostic factor for MCL outcome.

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Section: Resultsmentioning

confidence: 99%

Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

et al. 2016

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“…27 This inconsistent relationship of proliferation between different tumor compartments would require alteration of the assay parameters and may affect the clinical validity of the MCL35 assay in peripheral blood samples. Similarly, it is also not known whether the assay will have clinical validity in the rare leukemic non-nodal subtype of the disease.…”

Section: Discussionmentioning

confidence: 99%

New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies

Scott

Abrisqueta

Wright

et al. 2017

JCO

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Purpose Mantle cell lymphoma is an aggressive B-cell neoplasm that displays heterogeneous outcomes after treatment. In 2003, the Lymphoma/Leukemia Molecular Profiling Project described a powerful biomarker—the proliferation signature—using gene expression in fresh frozen material. Herein, we describe the training and validation of a new assay that measures the proliferation signature in RNA derived from routinely available formalin-fixed paraffin-embedded (FFPE) biopsies. Methods Forty-seven FFPE biopsies were used to train an assay on the NanoString platform, using microarray gene expression data of matched fresh frozen biopsies as a gold standard. The locked assay was applied to pretreatment FFPE lymph node biopsies from an independent cohort of 110 patients uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. Seventeen biopsies were tested across three laboratories to assess assay reproducibility. Results The MCL35 assay, which contained a 17-gene proliferation signature, yielded gene expression of sufficient quality to assign an assay score and risk group in 108 (98%) of 110 archival FFPE biopsies. The MCL35 assay assigned patients to high-risk (26%), standard-risk (29%), and low-risk (45%) groups, with different lengths of overall survival (OS): a median of 1.1, 2.6, and 8.6 years, respectively (log-rank for trend, P < .001). In multivariable analysis, these risk groups and the Mantle Cell Lymphoma International Prognostic Index were independently associated with OS ( P < .001 for both variables). Concordance of risk assignment across the three independent laboratories was 100%. Conclusion The newly developed and validated MCL35 assay for FFPE biopsies uses the proliferation signature to define groups of patients with significantly different OS independent of the Mantle Cell Lymphoma International Prognostic Index. Importantly, the analytic and clinical validity of this assay defines it as a reliable biomarker to support risk-adapted clinical trials.

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“…60 A pathogenic role of BCR signaling in MCL was further demonstrated by poor clinical outcome for patients with high LN BCR signature scores. 61 In addition to its central role in BCR signal propagation, BTK is activated upon ligation of crucial coreceptors such as CD40 and B-cell-activating factor receptor, as well as TLRs and chemokine receptors. 62,63 Hence, BTK inhibitors can have a profound effect by targeting multiple signaling pathways.…”

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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Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma

Abstract: Key Points Activation of BCR and canonical NF-κB signaling in the lymph node correlates with survival in MCL. Mutations and polymorphisms in BCR and NF-κB pathways may confer cell autonomous signaling and affect response to ibrutinib.

Cited by 133 publications

References 46 publications

Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

Decoding the DNA Methylome of Mantle Cell Lymphoma in the Light of the Entire B Cell Lineage

New Molecular Assay for the Proliferation Signature in Mantle Cell Lymphoma Applicable to Formalin-Fixed Paraffin-Embedded Biopsies

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

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