PXD056212-1

PXD056212 is an original dataset announced via ProteomeXchange.

Title	Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of Diffuse Large B Cell Lymphoma
Description	Differentiation of antigen-activated B cells into pro-proliferative germinal center (GC) B cells depends on the activity of the transcription factors MYC and BCL6, 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 derepression of BCL6 target genes and 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 strongly depends on DOT1L and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL.
HostingRepository	PRIDE
AnnounceDate	2025-10-15
AnnouncementXML	Submission_2025-10-14_22:12:49.186.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Liesbeth Hoekman
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-24 22:36:50	ID requested
⏵ 1	2025-10-14 22:12:49	announced

10.1182/BLOOD.2024025500;

submitter keyword: PRC2 targets,Differentiation-based therapy, Human, Astral, Diffuse Large B cell Lymphoma, DOT1L, EZH2, LC-MS/MS

onno bleijerveld
contact affiliation	Mass Spectrometry/Proteomics Facility, Netherlands Cancer Institute, Amsterdam, Netherlands.
contact email	o.bleijerveld@nki.nl
lab head
Liesbeth Hoekman
contact affiliation	The Netherlands Cancer Institute, Amsterdam, The Netherlands.
contact email	l.hoekman@nki.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD056212
     1. Label: PRIDE project
     2. Name: Targeting DOT1L and EZH2 synergizes in breaking the germinal center identity of Diffuse Large B Cell Lymphoma