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

Hatzi, Katerina; Geng, Huimin; Doane, Ashley S.; Meydan, Cem; LaRiviere, Reed; Cárdenas, Mariano; Duy, Cihangir; Shen, Hao; Vidal, María; Baslan, Timour; Mohammad, Helai P.; Kruger, Ryan G.; Shaknovich, Rita; Haberman, Ann M.; Inghirami, Giorgio; Lowe, Scott W.; Melnick, Ari

doi:10.1038/s41590-018-0273-1

Cited by 82 publications

(89 citation statements)

References 54 publications

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“…Demethylation of H3K4me1/2 is performed by the histone demethylase LSD1 . As expected, deletion of LSD1 induces an opposing phenotype to MLL2‐deletion, in that cell proliferation, germinal centers and plasma cell differentiation are reduced …”

Section: Histone Modifications and B Cell Differentiationmentioning

confidence: 52%

Epigenetic regulation of B cell fate and function during an immune response

Zhang

Good-Jacobson

2019

Immunological Reviews

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Summary The humoral immune response requires coordination of molecular programs to mediate differentiation into unique B cell subsets that help clear the infection and form immune memory. Epigenetic modifications are crucial for ensuring that the appropriate genes are transcribed or repressed during B cell differentiation. Recent studies have illuminated the changes in DNA methylation and histone post‐translational modifications that accompany the formation of germinal center and antibody‐secreting cells during an immune response. In particular, the B cell subset‐specific expression and function of DNA methyltransferases and histone‐modifying complexes that mediate epigenome changes have begun to be unravelled. This review will discuss the recent advances in this field, as well as highlight critical questions about the relationship between epigenetic regulation and B cell fate and function that are yet to be answered.

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Section: Histone Modifications and B Cell Differentiationmentioning

confidence: 52%

Epigenetic regulation of B cell fate and function during an immune response

Zhang

Good-Jacobson

2019

Immunological Reviews

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“…103 Since KMT2D mutations is highly upregulated and required for the GC reaction and repression of KMT2D target genes, its methyltransferase function is not required for this effect. 102 Of the four KDM5 genes, KDM5C and to a lesser extent KDM5A are highly expressed in GC B cells, FL, and DLBCL. Their loss-of-function was reported to rescue repression of KMT2D target genes in KMT2D-mutant lymphoma cells and selectively suppress the growth of these cells in vitro and in vivo.…”

Section: Core Epi G Ene Tic Mechanis Ms Driving G C-derived Lymphommentioning

confidence: 97%

“…87,101 The the BCL6 repression domain 2 (RD2). 21,87,102 MTA3 and CTBP may also be relevant BCL6 corepressors but this has not been validated outside of the cell line context. 84 Activation of BCL6 target genes in the light zone is mediated by the histone acetyltransferases CREBBP and EP300, and the histone methyltransferase KMT2D.…”

Section: Core Epi G Ene Tic Mechanis Ms Driving G C-derived Lymphommentioning

confidence: 99%

“…TET2-loss-of-function mutation results in failure to maintain enhancer 5hmC and loss of enhancer activating mark H3K27Ac with corresponding repression of the respective genes (red) upregulated and required for the GC reaction and repression of KMT2D target genes, its methyltransferase function is not required for this effect 102. (B) CREBBP maintains active enhancers (green) marked by H3K27Ac in mature B cells.…”

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confidence: 99%

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Germinal center‐derived lymphomas: The darkest side of humoral immunity

Mlynarczyk

Fontán

Melnick

2019

Immunological Reviews

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134

142

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Summary One of the unusual features of germinal center (GC) B cells is that they manifest many hallmarks of cancer cells. Accordingly, most B‐cell neoplasms originate from the GC reaction, and characteristically display abundant point mutations, structural genomic lesions, and clonal diversity from the genetic and epigenetic standpoints. The dominant biological theme of GC‐derived lymphomas is mutation of genes involved in epigenetic regulation and immune receptor signaling, which come into play at critical transitional stages of the GC reaction. Hence, mechanistic studies of these mutations reveal fundamental insight into the biology of the normal and malignant GC B cell. The BCL6 transcription factor plays a central role in establishing the GC phenotype in B cells, and most lymphomas are dependent on BCL6 to maintain survival, proliferation, and perhaps immune evasion. Many lymphoma mutations have the commonality of enhancing the oncogenic functions of BCL6, or overcoming some of its tumor suppressive effects. Herein, we discuss how unique features of the GC reaction create vulnerabilities that select for particular lymphoma mutations. We examine the interplay between epigenetic programming, metabolism, signaling, and immune regulatory mechanisms in lymphoma, and discuss how these are leading to novel precision therapy strategies to treat lymphoma patients.

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“…Epigenetic regulation of B cell differentiation is a nascent field, with understanding mostly limited to the roles of the methyltransferases EZH2 (Beguelin et al, 2013;Caganova et al, 2013), MLL2 (Zhang et al, 2015), demethylase LSD1 (Good-Jacobson, 2019; Haines et al, 2018;Hatzi et al, 2019) and acetyltransferase MOZ in germinal center (GC) biology.…”

Section: Introductionmentioning

confidence: 99%

The histone methyltransferase DOT1L is essential for humoral immune responses

Kealy

Pietro

Scheer

et al. 2019

Preprint

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Short running title: B cell responses require DOT1L. Abbreviations used: AID -activation-induced cytidine deaminase; ASCs -antibody-secreting cells; BCL6 -B cell lymphoma-6; CPM -counts per million; CTV -cell trace violet; DOT1Ldisruptor of telomeric silencing 1-like, EZH2 -enhancer of zeste homolog 2; FVS -fixable viability stain; H3K27me3 -trimethylation of lysine 27 on histone H3; Ig -immunoglobulin; KLH -Keyhole Limpet Hemocyanin; MLLr-ALL -Mixed Lineage Leukaemia-rearranged acute lymphoblastic leukaemia; NP -(4-Hydroxy-3-nitrophenyl)-acetyl; PRC2 -polycomb repressive complex 2; S1PR -sphingosine-1-phosphate receptor; Th cells -T helper cells. ABSTRACT Histone modifiers are essential molecular regulators that underpin the ability of immune cells to reprogram their gene expression during differentiation. The recruitment of the histone methyltransferase DOT1L induces oncogenic gene expression in a subset of B cell leukemia. Despite its importance, little is known about its role in the humoral immune system. Herein, we demonstrate that DOT1L is a critical regulator of B cell biology. Dot1l f/f Mb1 Cre/+ mice had a block in B cell development, culminating in a significant reduction of mature B cells in the periphery. Upon immunization or influenza infection, germinal centers failed to form in Dot1l f/f Cd23 Cre/+ mice. Consequently, immunized mice revealed that DOT1L was essential for the formation of B cell memory populations. Dot1l deletion significantly attenuated the formation of class-switched antibody-secreting cells in both T-dependent and T-independent responses. Transcriptome, pathway and histological analysis identified a key role for DOT1L in reprogramming gene expression for migration and localization during the initial stages of a humoral response. Together, these results demonstrate an essential role for DOT1L in antigen-dependent B cell differentiation and hence, in generating an effective and lasting humoral immune response.

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

Cited by 82 publications

References 54 publications

Epigenetic regulation of B cell fate and function during an immune response

Epigenetic regulation of B cell fate and function during an immune response

Germinal center‐derived lymphomas: The darkest side of humoral immunity

The histone methyltransferase DOT1L is essential for humoral immune responses

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