Αρχειοθήκη ιστολογίου

Παρασκευή 17 Νοεμβρίου 2017

CSIG-08. MUTANT IDH1 CO-OPERATES WITH ATRX LOSS TO DRIVE THE ALTERNATIVE LENGTHENING OF TELOMERE (ALT) PHENOTYPE IN GLIOMA

Abstract
A subset of human tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT activation. In these tumors, which include lower-grade astrocytomas (LGA) and secondary glioblastoma (sGBM), the ALT phenotype is associated with loss-of-function mutations in p53 and ATRX, although these mutations alone are insufficient to drive the process. Because LGA and sGBM also exhibit R132H IDH1 mutations, we examined the possible role of mutant IDH1 in driving ALT-based gliomagenesis. In p53/pRb-deficient human astrocytes, we found that neither expression of mutant IDH1 nor genetic deletion of ATRX was sufficient to drive the ALT phenotype. Combined expression of mutant IDH1 and loss of ATRX, however, resulted in the creation of tumorigenic cells with the ALT phenotype. The tumorigenic IDH1-mutant, ATRX-deficient ALT cells, as well as human IDH1-mutant LGA xenograft cells, consistently downregulated both RAP1 and XRCC1. Furthermore, exogenous re-expression of XRCC1 and/or RAP1 suppressed the ALT phenotype and tumor cell viability. Mechanistically, suppression of RAP1, a component of the telomere-capping shelterin complex, caused telomere dysfunction. Downregulation of XRCC1, a key component of the alternative non-homologous end joining (aNHEJ) pathway, suppressed aNHEJ-mediated lethal fusion of dysfunctional telomeres, and instead allowed IDH1-mutant, ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. These studies show that mutant IDH1 expression initiates telomeric dysfunction and alters DNA repair pathway preference at telomeres, and in doing so co-operates with p53 and ATRX loss to allow cells to overcome a critical bottleneck in gliomagenesis. Agents that alter the linkage between mutant IDH1 and DNA repair pathway preference may therefore be of particular interest in mutant IDH1 driven glioma.

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Medicine by Alexandros G. Sfakianakis,Anapafseos 5 Agios Nikolaos 72100 Crete Greece,00302841026182,00306932607174,alsfakia@gmail.com,

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