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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE138032 | 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 [Single cell RNA-Seq (10X Genomics)]

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RNA-seq profiles of germinal center B cells from spleens of wild-type and Il21r-deficient mice after immunization with NP-KLH

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Project description:Within germinal centers (GCs), complex and highly orchestrated molecular programs must balance proliferation, somatic hypermutation (SHM), class switch recombination (CSR) and selection to both provide effective humoral immunity and to protect against genomic instability and neoplastic transformation. In contrast to this complexity, GC B cells are canonically divided into two principal populations, dark zone (DZ) and light zone (LZ) cells. We now demonstrate that following selection in the LZ, B cells migrate to microniches within the canonical DZ that are sites of ongoing cell division. These proliferating DZ (DZp) cells then transit into the larger DZ to become differentiating DZ (DZd) cells before re-entering the LZ. Multidimensional analysis revealed distinct molecular programs in each population commensurate with observed compartmentization of non-compatable functions. These data provide a new three cell zone model that both orders critical GC functions and reveals essential molecular programs of humoral adaptive immunity.

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Comparison of NP specific high and low affinity IgG1 Light zone GC B cells

Project description:Despite the importance of memory B cells for protection from recurrent infection, how these cells are selected during germinal center (GC) reactions remains unclear. We show here that light zone (LZ) GC B cells with lower affinity BCRs express a less CD40 signature and relatively high levels of Bach2, being prone to enter the memory B cell pool. We also find that Bach2 contributes to memory B cell generation in a Blimp-1 independent manner and that its higher expression confers on LZ GC cells a more advantage for entering the memory B cell compartment. Thus, our data support an instructive model in which weak T cell help keeps Bach2 expression relatively high, thereby being predisposed to enter the memory pool.

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2016-05-09 | GSE77319 | GEO

The transcription factor Foxo1 controls germinal center B cell proliferation in response to T cell help

Project description:Germinal center (GC) B cells cycle between two states, the light zone (LZ) and the dark zone (DZ), and in the latter they proliferate and hypermutate their immunoglobulin genes. How this functional transition takes place is still controversial. In this study, we demonstrate that ablation of Foxo1 after GC development led to the loss of the DZ GC B cells and disruption of the GC architecture. Mechanistically, even upon provision of adequate T cell help, Foxo1-deficient GC B cells showed less proliferative expansion than controls. Moreover, we found that the transcription factor BATF was transiently induced in LZ GC B cells in a Foxo1-dependent manner and that deletion of BATF similarly led to GC disruption. Thus, our results are consistent with a model where the switch from the LZ to the DZ is triggered after receipt of T cell help, and suggest that Foxo1-mediated BATF up-regulation is at least partly involved in this switch.

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The RNA binding protein PTBP1 is necessary for B cell selection in germinal centres

Project description:Antibody affinity maturation occurs in germinal centres (GC) where B cells cycle between the light zone (LZ) and the dark zone. In the LZ GC B cells bearing immunoglobulins with the highest affinity for antigen receive positive selection signals from T helper cells that promotes their rapid proliferation. Here we show that the RNA binding protein PTBP1 is necessary for the progression of GC B cells through late S-phase of the cell cycle and for affinity maturation. PTBP1 is required for the expression of the c-MYC-dependent gene programme induced in GC B cells receiving T cell help and directly regulates the alternative splicing of transcripts increased during positive selection to promote anabolic metabolism and cell proliferation.

2017-12-06 | GSE100969 | GEO

STAT3 signaling in B cells controls germinal center zone organization and recycling [RNA-seq]

Project description:Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long-lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL-PCs, but negatively regulates MBC output.

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STAT3 signaling in B cells controls germinal center zone organization and recycling [ChIP-seq]

Project description:Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long- lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL- PCs, but negatively regulates MBC output.

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