Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
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Target Concepts:
Gene/Protein
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Query: UMLS:C0004135 (
ATM
)
13,001
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1
R132H
) are younger at diagnosis and live longer.
IDH1
mutations co-occur with other molecular lesions, such as 1p/19q codeletion, inactivating mutations in the tumor suppressor protein 53
(TP53
) gene, and loss-of-function mutations in
alpha thalassemia/mental retardation syndrome X-linked
gene (
ATRX
). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1
R132H
mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1
R132H
,
TP53
and
ATRX
inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1
R132H
in the context of TP53 and ATRX loss. We discovered that IDH1
R132H
expression in the genetic context of
ATRX
and
TP53
gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the
ataxia-telangiectasia
-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1
132H
glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.
...
PMID:IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. 3076 May 78
