ArticleCancer discovery2022
SETD2 Haploinsufficiency Enhances Germinal Center-Associated AICDA Somatic Hypermutation to Drive B-cell Lymphomagenesis.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 28 citations in OpenAlex.
- Establishment of Patient-Derived Xenotransplant and Cell Line Models for Canine B-Cell Lymphoma.Cells · 2026Article
- Blocking SETD2 Enhances the Therapeutic Efficiency of Menin Inhibitor in MLL-Fusion Leukemia.Cancer science · 2026Article
- Aberrant Kupffer-like differentiation of hematopoietic stem cell is critical for the MDS pathogenesis in Setd2-deficient mice.Cell death and differentiation · 2026Article
- The SETD2 L1609P mutation found in leukemia disrupts methyltransferase activity and reduces histone H3K36 trimethylation.The Journal of biological chemistry · 2026Article
- T follicular helper cells transiently unlock a plasticity state in germinal centre B cells during the humoral immune response.Nature cell biology · 2026Article
- Emerging role of SETD2 in the development and function of immune cells.Genes & diseases · 2025Review
- Chromatin Regulatory Targets for Anticancer Therapeutics.Chemical reviews · 2025Review
- Integrated Computational and Functional Screening Identifies G9a Inhibitors for SETD2-mutant Leukemia.Genomics, proteomics & bioinformatics · 2025Article
- Addressing Health Disparities in Hematologic Malignancies: from Genes to Outreach.Blood cancer discovery · 2025Review
- Metabolism and epigenetics in cancer: toward personalized treatment.Frontiers in endocrinology · 2025Review
- Development and validation of a prognostic model based on m6A-related lncRNAs to predict prognosis for papillary renal cell cancer patients.Scientific reports · 2024Article
- Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation.EMBO reports · 2024Article
- Epigenetic alterations and advancement of lymphoma treatment.Annals of hematology · 2024Review
- Single-cell sequencing reveals the heterogeneity of B cells and tertiary lymphoid structures in muscle-invasive bladder cancer.Journal of translational medicine · 2024Article
- Article
- The pathobiology of follicular lymphoma.Journal of clinical and experimental hematopathology : JCEH · 2023Article
- Drug addiction unveils a repressive methylation ceiling in EZH2-mutant lymphoma.Nature chemical biology · 2023Article
- Single-Cell RNA Sequencing Reveals Unique Alterations in the Immune Panorama and Treg Subpopulations in Mice during the Late Stages of Echinococcus granulosus Infection.Infection and immunity · 2023Article
- An Aged/Autoimmune B-cell Program Defines the Early Transformation of Extranodal Lymphomas.Cancer discovery · 2023Article
- SETD2-H3K36ME3: an important bridge between the environment and tumors.Frontiers in genetics · 2023Review
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Authors and funding
19 authors at 6 institutions in 4 countries.
Funding
Abstract
SETD2 is the sole histone methyltransferase responsible for H3K36me3, with roles in splicing, transcription initiation, and DNA damage response. Homozygous disruption of SETD2 yields a tumor suppressor effect in various cancers. However, SETD2 mutation is typically heterozygous in diffuse large B-cell lymphomas. Here we show that heterozygous Setd2 deficiency results in germinal center (GC) hyperplasia and increased competitive fitness, with reduced DNA damage checkpoint activity and apoptosis, resulting in accelerated lymphomagenesis. Impaired DNA damage sensing in Setd2-haploinsufficient germinal center B (GCB) and lymphoma cells associated with increased AICDA-induced somatic hypermutation, complex structural variants, and increased translocations including those activating MYC. DNA damage was selectively increased on the nontemplate strand, and H3K36me3 loss was associated with greater RNAPII processivity and mutational burden, suggesting that SETD2-mediated H3K36me3 is required for proper sensing of cytosine deamination. Hence, Setd2 haploinsufficiency delineates a novel GCB context-specific oncogenic pathway involving defective epigenetic surveillance of AICDA-mediated effects on transcribed genes. SIGNIFICANCE: Our findings define a B cell-specific oncogenic effect of SETD2 heterozygous mutation, which unleashes AICDA mutagenesis of nontemplate strand DNA in the GC reaction, resulting in lymphomas with heavy mutational burden. GC-derived lymphomas did not tolerate SETD2 homozygous deletion, pointing to a novel context-specific therapeutic vulnerability. This article is highlighted in the In This Issue feature, p. 1599.
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