2. Academic Validation
  3. GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma

GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma

  • Leukemia. 2024 Aug 8. doi: 10.1038/s41375-024-02325-4.
Michael Y He 1,  Kit I Tong 1,  Ting Liu 1,  Ryder Whittaker Hawkins 2 3,  Victoria Shelton 1,  Yong Zeng 1,  Mehran Bakhtiari 1,  Yufeng Xiao 4,  Guangrong Zheng 4,  Ali Sakhdari 5,  Lin Yang 1 6,  Wenxi Xu 1,  David G Brooks 1 2,  Rob C Laister 1,  Housheng Hansen He 1 6,  Robert Kridel 7 8 9 10
Affiliations

Affiliations

  • 1 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
  • 2 Department of Immunology, University of Toronto, Toronto, ON, Canada.
  • 3 Cell Biology Program, Hospital for Sick Children, Toronto, ON, Canada.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, USA.
  • 5 Laboratory Medicine and Pathobiology, University Health Network, Toronto, ON, Canada.
  • 6 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
  • 7 Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada. robert.kridel@uhn.ca.
  • 8 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada. robert.kridel@uhn.ca.
  • 9 Institute of Medical Science, University of Toronto, Toronto, ON, Canada. robert.kridel@uhn.ca.
  • 10 Department of Medicine, University of Toronto, Toronto, ON, Canada. robert.kridel@uhn.ca.
PMID: 39117798 DOI: 10.1038/s41375-024-02325-4
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.

Figures
Products
Inhibitors & Agonists
Other Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z