BCL6-Driven Lymphoma Is Dependent on LSD1 Corepression

Chromatin regulatory proteins play a central role in orchestrating the function of germinal centers (GC), where mature B cells must transiently repress genes involved in immune signaling, cell-cycle checkpoints, and DNA damage responses to undergo rapid proliferation and somatic hypermutation and allow for successful immunoglobulin affinity maturation. The transition through this hyperproliferative and genetically unstable state must be tightly regulated, and deregulation of this process can lead to malignant B-cell transformation. Based on prior observations showing loss of histone methylation at enhancers for genes repressed in GC B cells, Hatzi and colleagues investigated the role of histone demethylases in regulating GC formation and function. Among histone demethylases, LSD1 was most consistently upregulated in GCs, and conditional deletion of Lsd1 in GC B cells significantly impaired the formation of GCs and their ability to generate high-affinity antibodies. Lsd1-deficient B cells exhibited increased enhancer chromatin accessibility and increased expression of genes normally silenced in GC B cells that are also targets of the transcriptional repressor BCL6, a key regulator of GC function that is frequently translocated and constitutively expressed in B-cell lymphoma. BCL6 physically interacted with LSD1 and recruited LSD1 to its target genes, indicating that LSD1 acts in concert with BCL6 to facilitate proliferation and dampen immune signaling during humoral immune responses. Lsd1 deletion in mice with constitutive Bcl6 expression also rescued BCL6-driven GC hyperplasia, delayed lymphomagenesis, and prolonged survival, demonstrating that LSD1 is also required for BCL6-driven GC B-cell transformation. These findings raise the possibility that LSD1 could be a therapeutic target in BCL6-dependent lymphomas; however, catalytic inhibition of LSD1 did not have the same effect on GC formation as total LSD1 loss, and an LSD1 domain required for protein–protein interactions was instead required for lymphoma cell proliferation, raising the possibility that inhibitors that destabilize LSD1 may have activity in BCL6-driven lymphomas.

Hatzi K, Geng H, Doane AS, Meydan C, LaRiviere R, Cardenas M, et al. Histone demethylase LSD1 is required for germinal center formation and BCL6-driven lymphomagenesis. Nat Immunol 2019;20:86–96.

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