Qing Deng, University of Texas MD Anderson Cancer Center
Priya Lakra, University of Texas MD Anderson Cancer Center
Panhong Gou, University of Texas MD Anderson Cancer Center
Haopeng Yang, University of Texas MD Anderson Cancer Center
Cem Meydan, Weill Cornell Medicine
Matthew Teater, Weill Cornell Medicine
Christopher Chin, Weill Cornell Medicine
Wenchao Zhang, University of Texas MD Anderson Cancer Center
Tommy Dinh, University of Texas MD Anderson Cancer Center
Usama Hussein, University of Texas MD Anderson Cancer Center
Xubin Li, University of Texas MD Anderson Cancer Center
Estela Rojas, University of Texas MD Anderson Cancer Center
Weiguang Liu, University of Texas MD Anderson Cancer Center
Patrick K. Reville, University of Texas MD Anderson Cancer Center
Atish Kizhakeyil, University of Texas MD Anderson Cancer Center
Darko Barisic, Weill Cornell Medicine
Sydney Parsons, University of Texas MD Anderson Cancer Center
Ashley Wilson, University of Texas MD Anderson Cancer Center
Jared Henderson, University of Texas MD Anderson Cancer Center
Brooks Scull, Texas Children's Cancer Center
Channabasavaiah B. Gurumurthy, University of Nebraska Medical CenterFollow
Francisco Vega, University of Texas MD Anderson Cancer Center
Amy Chadburn, Weill Cornell Medicine
Branko Cuglievan, University of Texas MD Anderson Cancer Center
Nader Kim El-Mallawany, Texas Children's Cancer Center
Carl Allen, Texas Children's Cancer Center
Christopher Mason, Weill Cornell Medicine
Ari Melnick, Weill Cornell Medicine
Michael R. Green, University of Texas MD Anderson Cancer Center

Document Type

Article

Journal Title

Cancer Cell

Publication Date

2024

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.

ISSN

1878-3686

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