Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma

Abstract

A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower grade astrocytomas and secondary glioblastoma, we examined a hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb-deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the nonhomologous DNA end joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate reexpression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX-deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres by allowing IDH1-mutant ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis. Studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis and suggesting new therapeutic options to treat low-grade gliomas. .

Alternative lengthening of telomeres is the major telomere maintenance mechanism in astrocytoma with isocitrate dehydrogenase 1 mutation

“…Here we showed that the IDH1 R132H mutation is directly associated with a lack of ATRX expression and consequently, ALT as described previously [46]. In our sample, all tumors with ALT bear IDH1 R132H mutations and lost ATRX expression.…”

Alternative Lengthening of Telomeres in Pediatric Cancer: Mechanisms to Therapies

“…Work by Mukherjee et al investigated these mutations in the context of human ALT gliomas and found that IDH1 R132H mutations led to a consistent downregulation of a number of proteins, two of which being the Shelterin component RAP1, and the DNA damage repair protein XRCC1. The authors show that in the absence of ATRX, loss of both RAP1 and XRCC1 leads to an increase in ALT markers (26). Downregulation of RAP1 has previously been shown to lead to an increase in telomere dysfunction by end uncapping, however a previous study showed that following TALEN knockout RAP1 loss did not in itself lead to an increase in telomere dysfunction or tSCEs (40,41).…”

“…Nevertheless, mutations in other proteins have been described in ALT that are believed to be involved in, or may lead to the development of the ALT phenotype. These include mutations in histone H3.3, SMARCAL1, and IDH1 (24)(25)(26). Additional correlated mutations may indeed exist, however due to the lack of routine testing for ALT in clinic, many ALT cancers are likely never fully characterized.…”

“…Mutations in the isocitrate dehydrogenase enzyme (IDH1), specifically the R132H mutation, almost exclusively occur in gliomas and other cancers of the central nervous system. To date, no extensive work has been performed to quantify the prevalence of IDH1 mutations across the spectrum of ALT cancers, however, previous literature has shown that these mutations correlate strikingly with ALT status in certain tumor types (26). Work by Mukherjee et al investigated these mutations in the context of human ALT gliomas and found that IDH1 R132H mutations led to a consistent downregulation of a number of proteins, two of which being the Shelterin component RAP1, and the DNA damage repair protein XRCC1.…”

Molecular effects of dADD1 misexpression in chromatin organization and transcription

“…Mutations that affect the function of ATRX have been associated with several types of cancers, including glioblastoma and pancreatic cancer [20,21] and ATRX aberrant expression has been recently proposed as a marker of poor survival in soft tissue sarcomas [8]. On the contrary, higher levels of ATRX protein have not described in human cancers.…”