Selective Enhancer Dependencies in MYC-Intact and MYC-Rearranged Germinal Center B-cell Diffuse Large B-cell Lymphoma.

IF 11.5 Q1 HEMATOLOGY

Blood Cancer Discovery Pub Date : 2025-03-11 DOI:10.1158/2643-3230.BCD-24-0126

Ashwin R Iyer, Aishwarya Gurumurthy, Shih-Chun A Chu, Rohan Kodgule, Athalee R Aguilar, Travis Saari, Abdullah Ramzan, Jan Rosa, Juhi Gupta, Arvind Emmanuel, Cody N Hall, John S Runge, Anna B Owczarczyk, Jang W Cho, Matthew B Weiss, Rockwell Anyoha, Kristin Sikkink, Savanna Gemus, Charles P Fulco, Anamarija M Perry, Anthony D Schmitt, Jesse M Engreitz, Noah A Brown, Marcin P Cieslik, Russell J H Ryan

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Abstract

High expression of MYC and its target genes identify germinal center B-cell diffuse large B-cell lymphomas (GCB-DLBCL) associated with poor outcomes. We used CRISPR-interference profiling of human lymphoma cell lines to define essential enhancers in the MYC locus and non-immunoglobulin rearrangement partner loci, including a recurrent rearrangement between MYC and the BCL6 locus control region. GCB-DLBCL cell lines without MYC rearrangement are dependent on an evolutionarily-conserved enhancer we name "germinal center MYC enhancer 1" (GME-1), which is activated by the transcription factor complex of OCT2, OCA-B, and MEF2B, shows an active chromatin state in normal human and mouse germinal center B cells, and demonstrates selective acetylation and MYC promoter topological interactions in MYC-intact GCB-DLBCL biopsies. Whole-genome sequencing identified tandem copy gains of the GME-1 enhancer as a rare but recurrent event in DLBCL. Our findings shed new light on mechanisms that dysregulate MYC, a key driver of B cell malignancy.

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来源期刊

Blood Cancer Discovery Multiple-

CiteScore

12.70

自引率

1.80%

发文量

139

期刊介绍： The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.