Abstract P35: High-grade B-cell lymphomas with 11q aberrations show a dark zone expression profile similar to Burkitt lymphoma but with additional extension towards intermediate germinal center B-cells
Authors: Chteinberg Emil , Di Stefano Gioia , Loeffler-Wirth Henry , Staiger Annette , Hillebrecht Sina , Wagener Rabea , Bens Susanne , Oehl-Huber Kathrin , Dahlum Sonja , Abramov Dmitriy , Burkhardt Birgit , Louissaint Abner , Kurz Katrin , Horn Heike , Mottok Anja , Santi Raffaella , Oschlies Ilske , Klapper Wolfram , Schafernak Kristian , Zhang Yanming , Rosenwald Andreas , Binder Hans , Lim Megan S. , Ott German , Leoncini Lorenzo , Del-Val Coral , Siebert Reiner 
Published: March 2024

Abstract
High-grade B-cell lymphoma with 11q aberrations (HGBL-11q) is a type of aggressive B-cell lymphoma that shares morphological, immunophenotypic and gene expression features with Burkitt lymphoma (BL). HGBL-11q and BL differ in terms of the MYC translocation and typical landscapes of structural and small nucleotide variants. HGBL-11q harbours the name-giving 11q aberrations, and its mutational landscape is more similar to diffuse large B-cell lymphoma (DLBCL) than to BL. Despite these differences, BL and HGBL-11q have similar gene and protein expression profiles to normal B-cells in the germinal center (GC) dark zone (DZ). Recent single-cell RNA sequencing (scRNA-seq) studies have identified various subpopulations within the GC; in this study we aimed to explore the differences between HGBL-11q and BL based on the expression patterns of these different subpopulations within the GC. Transcriptional profiling by HTG EdgeSeq Pan B-Cell Lymphoma Panel, which includes 298 genes, was applied to FFPE sections of 7 BL, 26 HGBL-11q, 132 DLBCL, and two tonsils as controls. The panel was validated against RNAseq data available from overlapping samples of the ICGC MMML-Seq cohort, leaving 206 genes for further analyses.[OG(1] [EC2] [r3] From these, 60 genes overlapped with those included in expression signatures of GC subpopulations described in published scRNA-seq datasets. We investigated the ability of this reduced gene set to describe GC subpopulations in silico and investigated those gene sets proving robustness in the lymphomas dataset. Based on the expression of the 60 genes associated with specific GC populations, we also performed unsupervised clustering analyses using principal component analysis, t-distributed Stochastic Neighbor Embedding, and Uniform Manifold Approximation and Projection, as well as supervised DESeq2 analyses to identify differentially expressed genes. Out of all samples, 25 HGBL-11q and 50 DLBCL revealed a GC B-cell signature, along with all BLs. A comparison of the GC subpopulation expression patterns revealed heterogeneity in GCB-type DLBCL with a prevalent light zone expression pattern, while BL and HGBL-11q exhibited a quite homogenous pattern. BL showed a predominant DZ pattern, whereas HGBL-11q had high expression of DZ-associated genes similar to BL but also showed a considerable expression of genes associated with intermediate GC-associated genes. Cluster analysis with the 60 genes derived from the overlap with the GC population signatures showed that HGBL-11q segregates separately from BL and DLBCL notwithstanding the shared DZ pattern. Differential expression analysis confirmed that genes associated with intermediate GC B-cells, regardless of their chromosomal location, were higher in HGBL-11q compared to BLs, whereas ID3 was the top upregulated gene in BL as compared to HGBL-11q. In conclusion, HGBL-11q exhibits a DZ-related gene expression pattern similar to, but nevertheless distinct from, BL particularly in genes associated with GC intermediate B-cells.
Citation Format: Emil Chteinberg, Gioia Di Stefano, Henry Loeffler-Wirth, Annette Staiger, Sina Hillebrecht, Rabea Wagener, Susanne Bens, Kathrin Oehl-Huber, Sonja Dahlum, Dmitriy Abramov, Birgit Burkhardt, Abner Louissaint Jr, Katrin Kurz, Heike Horn, Anja Mottok, Raffaella Santi, Ilske Oschlies, Wolfram Klapper, Kristian Schafernak, Yanming Zhang, Andreas Rosenwald, Hans Binder, Megan S. Lim, German Ott, Lorenzo Leoncini, Coral Del-Val, Reiner Siebert. High-grade B-cell lymphomas with 11q aberrations show a dark zone expression profile similar to Burkitt lymphoma but with additional extension towards intermediate germinal center B-cells [abstract]. In: Proceedings of the Blood Cancer Discovery Symposium; 2024 Mar 4-6; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(2_Suppl):Abstract nr P35.