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Nat Immunol. 2019 Jan;20(1):86-96. doi: 10.1038/s41590-018-0273-1. Epub 2018 Dec 10.

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

Author information

1
Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY, USA.
2
Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
3
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
4
Institute for Computational Biomedicine, Dept. of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, USA.
5
High Throughput and Spectroscopy Resource Center, Rockefeller University, New York, NY, USA.
6
Cancer Epigenetics Department, GlaxoSmithKline, Collegeville, PA, USA.
7
Cancer Genetics Incorporated, Rutherford, NJ, USA.
8
Department of Laboratory Medicine, Department of Immunobiology Yale University School of Medicine, New Haven, CT, USA.
9
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
10
Howard Hughes Medical Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
11
Department of Medicine, Division of Hematology & Medical Oncology, Weill Cornell Medicine, New York, NY, USA. amm2014@med.cornell.edu.

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.

Comment in

PMID:
30538335
PMCID:
PMC6294324
DOI:
10.1038/s41590-018-0273-1
[Indexed for MEDLINE]
Free PMC Article

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