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EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE138037 | GEO | 2020/05/11

REPOSITORIES: GEO

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EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [ChIP-Seq]

Project description:The mechanism through which lymphoma-associated EZH2 gain-of-function mutations disrupt the immune system to initiate malignant transformation is poorly understood. Conditional expression of mutant Ezh2 in germinal center (GC) B-cells provides a competitive advantage to activated B-cells in expanding the GC light zone (LZ) that is not caused by failure to differentiate and exit the GC. Instead, the LZ enlargement is explained by reduced apoptosis of Ezh2 mutant centrocytes, aberrant LZ proliferation, and failure of these centrocytes to re-enter the dark zone (DZ). Ezh2 mutant GCs fail to engage T-cells and to undergo clonal diversification, exhibiting a reduced IgV mutation frequency. Hence the dominant competitive advantage effect of Ezh2 mutation during early stages of transformation is to uncouple GC B-cells from T-cell help checkpoint, which allows GC B-cells entering the LZ to persist and expand regardless of their immunoglobulin status, reflecting the biology of low-grade follicular lymphomas.

2020-05-11 | GSE138036 | GEO

EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [RNA-Seq]

2020-05-11 | GSE138032 | GEO

EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [Single cell RNA-Seq (10X Genomics)]

2020-05-11 | GSE138033 | GEO

EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche

Project description:EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche

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Mutant EZH2 Induces a Pre-malignant Lymphoma Niche by Reprogramming the Immune Response.

Project description:Follicular lymphomas (FLs) are slow-growing, indolent tumors containing extensive follicular dendritic cell (FDC) networks and recurrent EZH2 gain-of-function mutations. Paradoxically, FLs originate from highly proliferative germinal center (GC) B cells with proliferation strictly dependent on interactions with T follicular helper cells. Herein, we show that EZH2 mutations initiate FL by attenuating GC B cell requirement for T cell help and driving slow expansion of GC centrocytes that become enmeshed with and dependent on FDCs. By impairing T cell help, mutant EZH2 prevents induction of proliferative MYC programs. Thus, EZH2 mutation fosters malignant transformation by epigenetically reprograming B cells to form an aberrant immunological niche that reflects characteristic features of human FLs, explaining how indolent tumors arise from GC B cells.

| S-EPMC7298875 | biostudies-literature

EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [RNA-Seq]

Project description:EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [RNA-Seq]

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EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [ChIP-Seq]

Project description:EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [ChIP-Seq]

| PRJNA574277 | ENA

EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [Single cell RNA-Seq (10X Genomics)]

Project description:EZH2 mutations reprogram the immune response to yield a pre-malignant lymphoma niche [Single cell RNA-Seq (10X Genomics)]

| PRJNA574272 | ENA

EZH2 mutations are frequent and represent an early event in follicular lymphoma.

Project description:Gain of function mutations in the H3K27 methyltransferase EZH2 represent a promising therapeutic target in germinal center lymphomas. In this study, we assessed the frequency and distribution of EZH2 mutations in a large cohort of patients with follicular lymphoma (FL) (n = 366) and performed a longitudinal analysis of mutation during the disease progression from FL to transformed FL (tFL) (n = 33). Mutations were detected at 3 recurrent mutation hot spots (Y646, A682, and A692) in 27% of FL cases with variant allele frequencies (VAF) ranging from 2% to 61%. By comparing VAF of EZH2 with other mutation targets (CREBBP, MLL2, TNFRSF14, and MEF2B), we were able to distinguish patients harboring clonal EZH2 mutation from rarer cases with subclonal mutations. Overall, the high incidence of EZH2 mutations in FL and their stability during disease progression makes FL an appropriate disease to evaluate EZH2 targeted therapy.

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Project description:Classical Hodgkin lymphoma (cHL) has been identified with universal genetic alterations of chromosome 9p24.1, which contains PD-L1/PD-L2 genes. The amplification of 9p24.1 is associated with the increased expression of PD-L1 and PD-L2 on RS cells, which promotes their immune evasion, and subsequently makes cHL sensitive to PD-1 blockade. Several PD-1 inhibitors have shown significant efficacies with overall response rate (ORR) of 70%-90% in relapse/refractory (r/r) cHL and have acquired the approvals for this indication. Recently, more and more studies are conducted to investigate PD-1 blockade in earlier disease course and in combination with neo-agents or chemotherapy. Unlike cHL, non-Hodgkin lymphoma (NHL) consists of numerous subtypes harboring highly biological heterogeneity. Only a few subtypes have been shown to have genetic alteration of9p24.1 including primary mediastinal B cell lymphoma (PMBL), gray zone lymphoma (GZL) with features intermediate between diffuse large B cell lymphoma (DLBCL) and cHL, primary central nervous system lymphoma (PCNSL) and primary testicular lymphoma (PTL). Epstein-Barr virus (EBV)-associated lymphomas have a virally mediated overexpression of PD-L1, also making them sensitive to PD-1 blockade. Therefore, PD-1 inhibitors are less effective in most r/r NHL than in r/r cHL. Further understanding of the biological features of NHL and immune checkpoint inhibitors (ICPi) combined therapy is the research focus in the future. In this review, we outlined the recent progress of ICPi in lymphoma originating from clinical studies.

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