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Published on: March 2, 2014
GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma
Michael Y He1, Kit I Tong1, Ting Liu1
1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
Abstract:
Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.
Insights
Knocking out GNAS sensitizes resistant lymphomas to HDAC3 inhibition by triggering viral mimicry and interferon responses. Low GNAS expression may predict treatment response in lymphoma patients.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Selective HDAC3 inhibition shows promise for lymphomas with CREBBP mutations.
- Wild-type tumors typically resist HDAC3 inhibition, necessitating new therapeutic strategies.
Purpose of the Study:
- To identify genetic modifiers that sensitize resistant lymphoma cells to HDAC3 inhibition.
- To elucidate the mechanism of GNAS knockout-induced sensitization.
- To explore the clinical relevance of GNAS expression in lymphoma.
Main Methods:
- Genome-wide CRISPR screening was employed to identify sensitizing genes.
- Mechanistic studies involved assessing interferon responses, TBK1/IRF3 activation, and transposable element expression.
- Analysis of human lymphoma patient data correlated GNAS expression with therapeutic markers.
Main Results:
- GNAS knockout (KO) sensitized resistant lymphoma cells to HDAC3 inhibition.
- Sensitization was mediated by viral mimicry-related interferon responses, independent of canonical G-protein signaling.
- GNAS KO synergized with HDAC3 inhibition to enhance CD8+ T cell cytotoxicity.
- Low GNAS expression in human lymphoma patients correlated with high transposable element expression and interferon signaling.
Conclusions:
- GNAS KO induces sensitization to HDAC3 inhibition via viral mimicry and interferon pathways.
- Low GNAS expression is a potential biomarker for predicting response to HDAC3 inhibition in lymphoma, particularly in CREBBP wild-type cases.
- This study reveals a novel link between HDAC3 inhibition, viral mimicry, and lymphoma treatment.
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