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H3K27Ac mapping in DLBCL cell lines

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma and remains incurable in ~40% of patients. Coding-genome sequencing efforts identified several genes/pathways altered in this disease, including new potential therapeutic targets. However, the non-coding genome of DLBCL remains unexplored. Here we show that active superenhancers (SEs) are highly and specifically hypermutated in 99% of DLBCL samples. Such aberrant somatic hypermutation (ASHM) displays signatures of Activation Induced Deaminase activity and is linked to genes encoding B cell developmental regulators and oncogenes. To elucidate the functional consequences of SE-ASHM, we explored two recurrent mutational hotspots identified in the SEs linked to the BCL6 and BCL2 proto-oncogenes, but unmutated in normal GC B cells. These mutations prevent the binding and transcriptional downregulation by the transcriptional repressors BLIMP1 and NR3C1, respectively. Genetic correction of selected mutations restored repressor DNA binding as well as target gene transcriptional repression. Notably, this led to counter-selection of cells harboring corrected alleles, indicating oncogenic dependency from the SE mutations. This pervasive SE mutational mechanism reveals a new major set of genetic lesions deregulating gene expression, which expands the involvement of known oncogenes in DLBCL pathogenesis and identifies new deregulated gene targets of therapeutic relevance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182214 | GEO | 2022/04/26

REPOSITORIES: GEO

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Project description:Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCL with osseous localizations (O-DLBCL), including PB-DLBCL. 103 O-DLBCL patients were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin (COO) was determined by immunohistochemistry and gene-expression-profiling (GEP) using (extended)-NanoString/Lymph2Cx. Mutational profiles were identified with targeted next-generation deep-sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCL, were predominantly classified as GCB-phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx demonstrated significantly different GEP-clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P<0.001). Expression levels of 23 genes of two different targeted GEP-panels, indicated a centrocyte–like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB showed a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes, i.e. B2M, EZH2, IRF8, and TNFRSF14, compared to NO-DLBCL-GCB (P=0.031, P=0.010, P=0.047, and P=0.003). PB-DLBCL with its corresponding specific mutational profile were significantly associated with a superior overall survival compared to equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P=0.011). This study is the first to demonstrate that PB-DLBCL is characterized by a GCB-phenotype, with a centrocyte-like GEP-pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity and its specific mutational landscape holds potential for targeted therapies (e.g. EZH2-inhibitors). The NanoString analsyis consisted out of 219 probes for Lymph2Cx classifier (COO), MYC-activity GEP score, CNV-associated GEP signature, consensus clustering, and immune-ratio signature. This custome probeset was used to differentiate GEPs between osseous and non-osseos DLBCL of the GCB-phenotype.

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H3K27Ac mapping in DLBCL cell lines

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