The Epigenetic Basis of Diffuse Large B-Cell Lymphoma

Jiang, Yanwen; Melnick, Ari

doi:10.1053/j.seminhematol.2015.01.003

Cited by 56 publications

(39 citation statements)

References 77 publications

(158 reference statements)

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“…12 These observations open the pathway to specific DNA methyltransferase and histone methyltransferase inhibitors designed to erase aberrant epigenetic programming. 13 Several studies have investigated the genetic landscape of relapsing DLBCL patients and identified TP53, FOXO1, MLL3, CCND3, NFKBIZ, and STAT6 as top candidate genes for therapeutic resistance. 14 …”

Section: Patients With Early Relapsementioning

confidence: 99%

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

2016

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Although rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is the standard treatment for patients with diffuse large B-cell lymphoma (DLBCL),~30% to 50% of patients are not cured by this treatment, depending on disease stage or prognostic index. Among patients for whom R-CHOP therapy fails, 20% suffer from primary refractory disease (progress during or right after treatment) whereas 30% relapse after achieving complete remission (CR). Currently, there is no good definition enabling us to identify these 2 groups upon diagnosis. Most of the refractory patients exhibit double-hit lymphoma (MYC-BCL2 rearrangement) or double-protein-expression lymphoma (MYC-BCL2 hyperexpression) which have a more aggressive clinical picture. New strategies are currently being explored to obtain better CR rates and fewer relapses. Although young relapsing patients are treated with high-dose therapy followed by autologous transplant, there is an unmet need for better salvage regimens in this setting. To prevent relapse, maintenance therapy with immunomodulatory agents such as lenalidomide is currently undergoing investigation. New drugs will most likely be introduced over the next few years and will probably be different for relapsing and refractory patients. Learning Objectives• To be able to determine at diagnosis which DLBCL patients will likely experience treatment failure with R-CHOP • To understand the mechanisms that underlie resistance to standard treatments • To be able to assess the new proposed drugs, along with their efficacy for specific lymphoma populations such as those with double-hit lymphoma or double-protein-expression lymphoma • To learn more about potential solutions for refractory or relapsing patients

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Section: Patients With Early Relapsementioning

confidence: 99%

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

2016

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“…However, this instability can also contribute to malignant transformation, and epigenetic changes remain a major feature of DLBCL cells. Genes that function as epigenetic regulators are commonly mutated in DLBCL, with less intratumoral heterogeneity than other cancer‐driving mutations, suggesting a role in early tumorgenesis …”

Section: Introductionmentioning

confidence: 99%

Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma

et al. 2017

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Global hypomethylation has been linked to disease progression in several cancers, but has not been reported for Diffuse Large B Cell Lymphoma (DLBCL). This study aimed to assess global methylation in DLBCL and describe its prognostic value. Mean LINE1 methylation, a validated surrogate measure for global methylation, was measured in DNA from 67 tumor biopsies. Additionally, cell-free circulating DNA (cfDNA) in plasma samples from 74 patients was tested to assess the feasibility of global hypomethylation as a biomarker in liquid biopsies. LINE1 methylation was assessed using a commercially available kit, based on pyrosequencing of PCR amplified bisulfite-treated DNA. Global hypomethylation was detected in a subset of cases and was associated with poor overall survival in both tumor biopsies (P = .001) and cfDNA (P = .009). It was the strongest risk factor in multivariate analysis in both biopsies (HR: 10.65, CI: 2.03-55.81, P = .005) and cfDNA (HR: 11.87, CI: 2.80-50.20, P = .001), outperforming conventional clinical risk factors. Finally, hierarchical cluster analyses were performed for the cfDNA samples using previously published gene-specific methylation data. This analysis shows that global hypomethylation co-occurs with other epigenetic abnormalities, including DAPK1 promoter hypermethylation. In conclusion, we have shown that global hypomethylation is strongly associated with poor survival in DLBCL both when present in tumor biopsy DNA and when detected in plasma cfDNA, and has potential for clinical application as a prognostic biomarker.

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“…In B-NHL, genetic and epigenetic alterations create tumor phenotypes that are protected against immune cytolysis. [1][2][3][4][5][6][7] Immune escape also evolves through the concerted upregulation of gene expression. 8 For example, the B-NHL subtypes FL and DLBCL upregulate the expression of genes involved in the PD1/PDL1-2 axis, the CTLA4 ligand axis, the biosynthesis of immunosuppressive Galectin 3, and the genes IDO1, VEGFA, PGE2, IL10, and HGF, among several others.…”

Section: Introductionmentioning

confidence: 99%

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

et al. 2016

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Non-Hodgkin B-cell lymphoma (B-NHL) are aggressive lymphoid malignancies that develop in patients due to oncogenic activation, chemo-resistance, and immune evasion. Tumor biopsies show that B-NHL frequently uses several immune escape strategies, which has hindered the development of checkpoint blockade immunotherapies in these diseases. To gain a better understanding of B-NHL immune editing, we hypothesized that the transcriptional hallmarks of immune escape associated with these diseases could be identified from the meta-analysis of large series of microarrays from B-NHL biopsies. Thus, 1446 transcriptome microarrays from seven types of B-NHL were downloaded and assembled from 33 public Gene Expression Omnibus (GEO) datasets, and a method for scoring the transcriptional hallmarks in single samples was developed. This approach was validated by matching scores to phenotypic hallmarks of B-NHL such as proliferation, signaling, metabolic activity, and leucocyte infiltration. Through this method, we observed a significant enrichment of 33 immune escape genes in most diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) samples, with fewer in mantle cell lymphoma (MCL) and marginal zone lymphoma (MZL) samples. Comparing these gene expression patterns with overall survival data evidenced four stages of cancer immune editing in B-NHL: non-immunogenic tumors (stage 1), immunogenic tumors without immune escape (stage 2), immunogenic tumors with immune escape (stage 3), and fully immuno-edited tumors (stage 4). This model complements the standard international prognostic indices for B-NHL and proposes that immune escape stages 3 and 4 (76% of the FL and DLBCL samples in this data set) identify patients relevant for checkpoint blockade immunotherapies.

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The Epigenetic Basis of Diffuse Large B-Cell Lymphoma

Cited by 56 publications

References 77 publications

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

Diffuse large B-cell lymphoma: R-CHOP failure—what to do?

Global hypomethylation is an independent prognostic factor in diffuse large B cell lymphoma

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

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