Mutant ATRX: uncovering a new therapeutic target for glioma

ABSTRACT

Introduction: ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3. ATRX mutations are widely distributed in glioma, and correlate with alternative lengthening of telomeres (ALT) development, but they also affect other cellular functions related to epigenetic regulation.

Areas covered: We discuss the main molecular characteristics of ATRX, from its various functions in normal development to the effects of its loss in ATRX syndrome patients and animal models. We focus on the salient consequences of ATRX mutations in cancer, from a clinical to a molecular point of view, focusing on both adult and pediatric glioma. Finally, we will discuss the therapeutic opportunities future research perspectives.

Expert opinion: ATRX is a major component of various essential cellular pathways, exceeding its functions as a histone chaperone (e.g. DNA replication and repair, chromatin higher-order structure regulation, gene transcriptional regulation, etc.). However, it is unclear how the loss of these functions in ATRX-null cancer cells affects cancer development and progression. We anticipate new treatments and clinical approaches will emerge for glioma and other cancer types as mechanistic and molecular studies on ATRX are only just beginning to reveal the many critical functions of this protein in cancer.

KEYWORDS:

• ATRX
• alpha-thalassemia X-linked mutant retardation syndrome
• high-grade glioma
• alternative lengthening of telomeres
• DAXX
• DNA damage
• histone chaperone
• SWI/SNF2

Article highlights

• ATRX is a chromatin remodeling protein whose main function is the deposition of the histone variant H3.3, mainly in facultative and constitutive heterochromatin.

• Mutations in ATRX were found in various cancers and the occurrence of these mutations has a close association with the development of the alternative lengthening of telomeres (ALT) mechanism, a recombination-based telomere maintenance mechanism (TMM).

• ATRX mutations occur in some types of glioma, eliciting changes in the features of the cancer, from molecular to clinical perspectives. The occurrence of mutations in epigenetic regulators is frequent in glioma, indicating that epigenetic reprogramming is a critical event in glioma development.

• In addition to the association of ATRX with the ALT mechanism, ATRX has a broad spectrum of functions related with its ability to reshape the epigenetic state of the cells.

• Cancer cells harboring ATRX mutations exhibit chromatin instability and impaired DNA damage response, which make them vulnerable to DNA damaging treatments. While in animal models ATRX-mutant gliomas progress faster than the ATRX wild-type counterparts, they are more responsive to DNA damaging treatments. There is also a correlation between the presence of ATRX mutations and extended survival in treated patients.

• Although ATRX has been associated with a wide variety of functions, it remains to be addressed how the loss of these functions in ATRX-null cancers cells affect cancer development and progression.

• ATRX-mutated cancer cells share molecular characteristics that can be exploited to develop specific therapeutic approaches. DNA damage, chromatin instability, immune response, and senescence induction emerge as the main vulnerabilities in these cells.

This box summarizes key points contained in the article.

Declaration of interests

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by National Institutes of Health/National Institute of Neurological Disorders & Stroke (NIH/NINDS) Grants R01-NS074387, R21-NS091555, R37-NS094804 and BCured grant to M.G.C.; NIH/NINDS Grants R01-NS076991, R01-NS082311, R01-096756, NIH/NIBIB R01-EB022563 and NIH/NCI U01CA224160-01 to P.R.L.; Leah’s Happy Heart Foundation, Chad Tough Foundation, the University of Michigan Comprehensive Cancer Center, and The Phase One Foundation to M.G.C. and P.R.L.; the Department of Neurosurgery, University of Michigan Medical School. MGC is supported in part by the Cancer Biology Training Grant, NIH/NCI T32-CA009676.