Faculty, Staff and Student Publications

Publication Date

4-8-2024

Journal

Cancer Cell

DOI

10.1016/j.ccell.2024.02.011

PMID

38458188

PMCID

PMC11003852

PubMedCentral® Posted Date

4-8-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family, and NF-κB. Loss of activity for these factors phenocopied aberrant BCL6 activity within murine centrocytes and human Burkitt lymphoma cells. SMARCA4 therefore facilitates chromatin accessibility for TFs that shape centrocyte trajectories, and loss of fine-control of these programs biases toward centroblast cell-fate, GC hyperplasia and lymphoma.

Keywords

Animals, Humans, Mice, Chromatin, DNA Helicases, Haploinsufficiency, Hyperplasia, Lymphoma, B-Cell, Nuclear Proteins, Transcription Factors

Published Open-Access

yes

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