Year: 2022
Type: conference-abstract
Abstract: ATRX is a key chromatin regulator, which is mutated in large subsets of both adult and pediatric gliomas. Despite being a common mutation, little is known about the biological ramifications of ATRX deficiency. Recently, it has been demonstrated that ATRX deficiency drives increased replication stress, DNA damage, and global epigenetic dysregulation. Despite these advances, little is known about the impact of ATRX deficiency on the tumor microenvironment (TME). In order to explore the impact of ATRX deficiency on the TME we utilized the RCAS/nTVa system to generate a novel murine model of ATRX deficient glioma. Mice bearing allografts of these tumors displayed significantly increased survival relative to the ATRX intact lines. This survival benefit persisted in Nu/nu mice, which lack an adaptive immune system, but not in SCID mice, which lack both adaptive and innate immunity. Bulk RNA sequencing revealed the ATRX deficient tumors displayed increased expression of inflammatory and innate immune gene sets, and western blotting revealed increased phosphorylation of tank binding kinase 1 (TBK1), a key innate immune regulator. Multiplex cytokine analysis of conditioned media also revealed increased expression of inflammatory cytokines such as CCL2, CCL5, and CXCL10 in the supernatant of ATRX deficient cell lines. Taken together, these results indicate that ATRX deficiency can drive innate immune activation, and that this activation can increase survival in vivo. Further exploration is needed to characterize the upstream drivers of TBK1 activation and elucidate alterations to immune cell infiltration in ATRXdeficient tumors.
Source: Neuro-Oncology
Authors: Benjamin Whitfield, Jason Huse, David Irvin, Sharvari Dharmaiah, Prit Benny Malgulwar, Hannah Roberts
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4309015009