(B) Unsupervised clustering of the gene expression profiles generated from DZ and LZ segmented ROIs according to a custom mRNA panel, showing the separation of DZ and LZ ROIs based on the expression of the 53 deregulated genes. Identification of a DZ/LZ Microenvironment Differential Signature by Digital Spatial Profiling on Reactive Lymph Node ROIs (A) Multiplexed immunofluorescence for CD20 (red signal), nerve growth factor receptor (NGFR)/CD271 (cyan signal), smooth muscle actin (SMA, green signal), and Syto83 (blue signal) has been performed to drive selection of ROIs corresponding to LZ and DZ, for segmentation and gene expression analysis. The report offers new insight into the GC microenvironment, hinting at a DZ microenvironment of origin in DH lymphomas. The clustering analysis was also performed using a 25-genes signature composed of genes positively enriched in the non-B, stromal sub-compartments, for the first time achieving DZ/LZ discrimination based on stromal/immune features. The subgroups differed in the distribution of DH cases and survival, with most DH displaying a distinct DZ-like profile. According to the DZ/LZ signature, the GC-related lymphomas were sub-classified into two clusters. The spatially resolved 53-genes signature, comprising key genes of the DZ mutational machinery and LZ immune and mesenchymal milieu, was applied to the transcriptomes of 543 GC-related diffuse large B cell lymphomas and double-hit (DH) lymphomas. We applied digital spatial profiling for 87 immune and stromal genes to lymph node germinal center (GC) dark- and light-zone (DZ/LZ) regions of interest to obtain a differential signature of these two distinct microenvironments.
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