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TOPLINE: 

Germinal center B-cell–like diffuse large B-cell lymphomas (GCB-DLBCLs) show dependence on DOT1L and EZH2, with combined targeting offering potential as an alternative differentiation-based therapy. DOT1L and EZH2 work cooperatively to repress polycomb repressive complex 2 (PRC2) target genes, maintaining the pro-proliferative germinal center B-cell identity of DLBCL.

METHODOLOGY:  

• Researchers from multiple institutions conducted the investigation.
• Analysis focused on the combined effects of DOT1L and EZH2 targeting in GCB-DLBCL.
• Investigators examined the synergistic potential of targeting both DOT1L and EZH2 in breaking germinal center identity.
• The research team evaluated the impact on pro-proliferative GCB identity maintenance in DLBCL.

TAKEAWAY:  

• Combined treatment with DOT1L and EZH2 inhibitors resulted in upregulation of BCL6 target genes and suppression of myelocytoma target genes.
• Researchers observed that GCB-DLBCLs undergo a cell identity crisis, losing their pro-proliferative characteristics and partially transitioning to plasma cell differentiation.
• The investigation demonstrated that dual targeting of DOT1L and EZH2 effectively prevented human GCB-DLBCL xenograft growth in vivo.
• According to the authors, GCB-DLBCLs exhibit strong dependence on DOT1L and EZH2, suggesting potential for combination targeting as an alternative treatment approach.

IN PRACTICE:

“Combined epidrugging 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 DOTIL and EZH2 and that combined targeting of both epigenetic writers may provide an alternative differentiation-based treatment modality for GCB-DLBCL,” wrote the authors of the study.

SOURCE:

The study was led by Camiel Göbel and Rachele Niccolai, Netherlands Cancer Institute, Amsterdam. It was published online on April 17 in Blood.

LIMITATIONS:

The researchers noted that when GCB-DLBCLs lose their pro-proliferative germinal center identity and partially undergo plasma cell differentiation, this state is associated with poor survival outcomes.

DISCLOSURES:

The study was supported by grants from the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sports. Onno B. Bleijerveld and Liesbeth Hoekman received support from the Dutch NWO X-omics Initiative. Others had no disclosures.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.