Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of Diffuse Large B Cell Lymphoma

Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factor MYC and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GC B cells and closely resemble their ce...

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Hlavní autori: Göbel, Camiel, Niccolai, Rachele, de Groot, Marnix H.P., Jayachandran, Jayashree, Traets, Joleen, Morris, Ben, Song, Ji-Ying, Azarang, Leyla, Kasa, Eirini, de Groot, Daniel, Kreft, Maaike, Kersten, Marie José, Aslam, Muhammad A., van Leeuwen, Fred, Jacobs, Heinz
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Vydavateľské údaje: Cold Spring Harbor Laboratory 08.06.2024
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Cancer Biology
ISSN:2692-8205
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Abstract Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factor MYC and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GC B cells and closely resemble their cell of origin. Given the dependency of GC B cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCL cell lines and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the suppression of MYC target genes. The sum of all these alterations results in a ‘cell-identity crisis,’ wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strictly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL. MYC-driven GCB-DLBCL depends on DOT1L and EZH2 and combined targeting provides an alternative differentiation-based therapy. DOT1L and EZH2 cooperatively repress PRC2 target genes which is essential for acquiring a plasma cell-like state in GC B cell-like DLBCL.
AbstractList Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factor MYC and the epigenetic writers DOT1L and EZH2. GCB-like Diffuse Large B Cell Lymphomas (GCB-DLBCLs) arise from GC B cells and closely resemble their cell of origin. Given the dependency of GC B cells on DOT1L and EZH2, we investigated the role of these epigenetic regulators in GCB-DLBCL cell lines and observed that GCB-DLBCLs synergistically depend on the combined activity of DOT1L and EZH2. Mechanistically, inhibiting both enzymes led to enhanced derepression of PRC2 target genes compared to EZH2 single treatment, along with the suppression of MYC target genes. The sum of all these alterations results in a ‘cell-identity crisis,’ wherein GCB-DLBCLs lose their pro-proliferative GC identity and partially undergo plasma cell differentiation, a state associated with poor survival. In support of this model, combined epi-drugging of DOT1L and EZH2 prohibited the outgrowth of human GCB-DLBCL xenografts in vivo. We conclude that the malignant behavior of GCB-DLBCLs strictly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL. MYC-driven GCB-DLBCL depends on DOT1L and EZH2 and combined targeting provides an alternative differentiation-based therapy. DOT1L and EZH2 cooperatively repress PRC2 target genes which is essential for acquiring a plasma cell-like state in GC B cell-like DLBCL.
Author Traets, Joleen
Kersten, Marie José
Morris, Ben
Jayachandran, Jayashree
Göbel, Camiel
de Groot, Marnix H.P.
Kreft, Maaike
Jacobs, Heinz
Song, Ji-Ying
de Groot, Daniel
Azarang, Leyla
Niccolai, Rachele
Kasa, Eirini
Aslam, Muhammad A.
van Leeuwen, Fred
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  organization: Biostatistics Center, Netherlands Cancer Institute
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  organization: Division of Tumor Biology and Immunology, Netherlands Cancer Institute
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  fullname: Aslam, Muhammad A.
  organization: Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University
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  orcidid: 0000-0002-7267-7251
  surname: van Leeuwen
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  surname: Jacobs
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Snippet Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factor MYC and...
SourceID biorxiv
SourceType Open Access Repository
SubjectTerms Cancer Biology
Title Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of Diffuse Large B Cell Lymphoma
URI https://www.biorxiv.org/content/10.1101/2024.06.05.597556
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