TitleHistone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis.
Publication TypeJournal Article
Year of Publication2019
AuthorsHatzi, Katerina, Geng Huimin, Doane Ashley S., Meydan Cem, LaRiviere Reed, Cardenas Mariano, Duy Cihangir, Shen Hao, Vidal Maria Nieves Cal, Baslan Timour, Mohammad Helai P., Kruger Ryan G., Shaknovich Rita, Haberman Ann M., Inghirami Giorgio, Lowe Scott W., and Melnick Ari M.
JournalNat Immunol
Volume20
Issue1
Pagination86-96
Date Published2019 01
ISSN1529-2916
KeywordsAnimals, B-Lymphocytes, Carcinogenesis, CRISPR-Cas Systems, DNA, Intergenic, Germinal Center, Histone Demethylases, Hyperplasia, Immunological Synapses, Introns, Lymphoma, Mice, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins c-bcl-6
Abstract

<p>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.</p>

DOI10.1038/s41590-018-0273-1
Alternate JournalNat Immunol
PubMed ID30538335
PubMed Central IDPMC6294324
Grant ListK99 CA212276 / CA / NCI NIH HHS / United States
P01 CA013106 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R35 CA220499 / CA / NCI NIH HHS / United States