Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis Journal Article

Authors: Hatzi, K.; Geng, H.; Doane, A. S.; Meydan, C.; LaRiviere, R.; Cardenas, M.; Duy, C.; Shen, H.; Vidal, M. N. C.; Baslan, T.; Mohammad, H. P.; Kruger, R. G.; Shaknovich, R.; Haberman, A. M.; Inghirami, G.; Lowe, S. W.; Melnick, A. M.
Article Title: Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis
Abstract: Germinal center (GC) B cells feature repression of many gene enhancers to establish their characteristic transcriptome. Here we show that conditional deletion of Lsd1 in GCs significantly impaired GC formation, associated with failure to repress immune synapse genes linked to GC exit, which are also direct targets of the transcriptional repressor BCL6. We found that BCL6 directly binds LSD1 and recruits it primarily to intergenic and intronic enhancers. Conditional deletion of Lsd1 suppressed GC hyperplasia caused by constitutive expression of BCL6 and significantly delayed BCL6-driven lymphomagenesis. Administration of catalytic inhibitors of LSD1 had little effect on GC formation or GC-derived lymphoma cells. Using a CRISPR-Cas9 domain screen, we found instead that the LSD1 Tower domain was critical for dependence on LSD1 in GC-derived B cells. These results indicate an essential role for LSD1 in the humoral immune response, where it modulates enhancer function by forming repression complexes with BCL6. © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
Keywords: controlled study; protein expression; unclassified drug; human cell; nonhuman; flow cytometry; cell proliferation; animal cell; mouse; animal experiment; animal model; genetic association; intron; cell differentiation; cell population; b lymphocyte; carcinogenesis; germinal center; lymphocyte differentiation; plasma cell; messenger rna; chromatin immunoprecipitation; splenomegaly; lymphoma; immunoblotting; tumor immunity; protein bcl 6; memory cell; humoral immunity; cre recombinase; loss of function mutation; cell expansion; interleukin 12; chromatin assembly and disassembly; rna sequence; spleen cell; histone demethylase; diffuse large b cell lymphoma; histone demethylation; guide rna; human; priority journal; article; histone demethylase lsd1; tfh cell
Journal Title: Nature Immunology
Volume: 20
Issue: 1
ISSN: 1529-2908
Publisher: Nature Publishing Group  
Date Published: 2019-01-01
Start Page: 86
End Page: 96
Language: English
DOI: 10.1038/s41590-018-0273-1
PROVIDER: scopus
PMCID: PMC6294324
PUBMED: 30538335
Notes: Nat. Immunol. -- Export Date: 2 January 2019 -- Article -- CODEN: NIAMC C2 - 30538335 -- Source: Scopus
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MSK Authors
  1. Scott W Lowe
    144 Lowe
  2. Timour Baslan
    15 Baslan