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SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [human ATAC-Seq]

ABSTRACT: ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows 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 CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- 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 in mice. Remarkably, follicular lymphoma patients 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 lymphomas in ARID1A-mutant patients through 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE254588 | GEO | 2024/02/02

REPOSITORIES: GEO

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ARID1A Orchestrates SWI/SNF-mediated Sequential Binding of Transcription Factors and Its Deficiency Drives Pre-memory B-cell Fate and Lymphomagenesis [Arid1a_multiome]

Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows 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 towards immature IgM+CD80-PDL2- 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 in mice. Remarkably, follicular lymphoma patients 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 lymphomas in ARID1A-mutant patients through 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.

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SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [mouse RNA-Seq]

Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows 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 CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- 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 in mice. Remarkably, follicular lymphoma patients 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 lymphomas in ARID1A-mutant patients through 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.

2024-02-02 | GSE254595 | GEO

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SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [human RNA-Seq]

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SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [human Mnase-Seq]

Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows 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 CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- 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 in mice. Remarkably, follicular lymphoma patients 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 lymphomas in ARID1A-mutant patients through 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.

2024-02-02 | GSE254591 | GEO

SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [human FHD286 ATAC-Seq]

Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows 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 CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- 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 in mice. Remarkably, follicular lymphoma patients 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 lymphomas in ARID1A-mutant patients through 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.

2024-02-02 | GSE254589 | GEO

SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [human ChIP-seq]

Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows 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 CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- 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 in mice. Remarkably, follicular lymphoma patients 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 lymphomas in ARID1A-mutant patients through 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.

2024-03-22 | GSE262093 | GEO

SWI/SNF Chromatin Remodeling Complex Orchestrates Sequential Binding of Key Transcription Factors in B Cells and Restricts Aggressive Lymphoma [human CUT&RUN]

Project description:ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. Our study shows 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 CD signaling. The absence of ARID1A tilts GC cell-fate towards immature IgM+CD80-PDL2- 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 in mice. Remarkably, follicular lymphoma patients 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 lymphomas in ARID1A-mutant patients through 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.

2024-03-22 | GSE262094 | GEO

Molecular targets of glucocorticoids that elucidate their therapeutic efficacy in aggressive lymphomas

Project description:Prednisone is anti-inflammatory glucocorticoid (GC), and GC-based therapy is most used combination chemotherapy for treating aggressive B-cell lymphomas. However, there are still gaps in our understanding of specific mechanism of GCâ€™s action for its cytotoxicity. By performing multi-omics approaches, we identified new GR targets and how these targets control the b-cell receptor signaling networks, providing a mechanistic framework upon which to base combination therapies.

2024-05-02 | PXD041891 | Pride

Arid1a-dependent canonical BAF complex suppresses inflammatory programs to drive efficient GC B cell responses [CUT&TAG]

Project description:Differentiating B cells in germinal centers (GC) require tightly coordinated transcriptional and epigenetic transitions to generate efficient humoral immune responses. The mammalian BAF (Brg1/Brm-associated factor) complexes are major regulators of nucleosomal remodeling, crucial for cellular differentiation and development, and are commonly mutated in several cancers, including GC-derived B cell lymphomas. However, the specific roles of distinct BAF complexes in GC B cell biology and the generation of functional humoral immune responses are not well-understood. Here, we show that the Arid1a-dependent canonical BAF (cBAF) complex is indispensable for generatingon of fully mature GCs and high affinity humoral immune responses. While Arid1a-deficient B cells undergo activation to initiate GC responses, they fail to sustain the GC program, resulting incausing premature GC collapse. Mechanistically, Arid1a-dependent cBAF activity establishes permissive chromatin landscapes at several thousand genomic regions during B cell activation and isare concomitantly required to suppress inflammatory gene programs to maintain transcriptional fidelity in early GC B cells. Interestingly, the inflammatory signatures instigated by Arid1a- deficiency in early GC B cells recruits neutrophils and inflammatory monocytes, and eventually disrupts GC homeostasis. Remarkably, dampening of inflammatory cues with anti-inflammatory glucocorticoid receptor signaling rescues GC B cell differentiation of Arid1a-deficient B cells, thus highlighting a critical role of inflammation in impeding GC responses. In sum, our work identifies essential functions of Arid1a-dependent BAF activity in promoting efficient GC responses. These findings further support recent paradigms uncovering a deterministic role of unrestrained inflammation in obstructing GC responses, common in patients with severe bacterial and viral infections.

2024-07-31 | GSE267944 | GEO

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