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Cancer Cell ; 42(4): 583-604.e11, 2024 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-38458187

RESUMO

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.


Assuntos
Linfoma , Células B de Memória , Animais , Humanos , Camundongos , Proteínas de Ligação a DNA/genética , Linfoma/genética , Mutação , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
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