气候变化领域集成服务门户(CCPortal): Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells

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DOI	10.1073/pnas.2016833118
	Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells
	Owen N.; Minko I.G.; Moellmer S.A.; Cammann S.K.; Lloyd R.S.; Amanda K. McCullough
发表日期	2021
ISSN	00278424
卷号	118 期号:11
英文摘要	Human clinical trials suggest that inhibition of enzymes in the DNA base excision repair (BER) pathway, such as PARP1 and APE1, can be useful in anticancer strategies when combined with certain DNA-damaging agents or tumor-specific genetic deficiencies. There is also evidence suggesting that inhibition of the BER enzyme 8-oxoguanine DNA glycosylase-1 (OGG1), which initiates repair of 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG) and 2,6-diamino-4-hydroxy-5-formamidopyrimidine (Fapy-dG), could be useful in treating certain cancers. Specifically, in acute myeloid leukemia (AML), both the RUNX1-RUNX1T1 fusion and the CBFBMYH11 subtypes have lower levels of OGG1 expression, which correlate with increased therapeutic-induced cell cytotoxicity and good prognosis for improved, relapse-free survival compared with other AML patients. Here we present data demonstrating that AML cell lines deficient in OGG1 have enhanced sensitivity to cytarabine (cytosine arabinoside [Ara-C]) relative to OGG1- proficient cells. This enhanced cytotoxicity correlated with endogenous oxidatively-induced DNA damage and Ara-C-induced DNA strand breaks, with a large proportion of these breaks occurring at common fragile sites. This lethality was highly specific for Ara-C treatment of AML cells deficient in OGG1, with no other replication stress-inducing agents showing a correlation between cell killing and low OGG1 levels. The mechanism for this preferential toxicity was addressed using in vitro replication assays in which DNA polymerase δ was shown to insert Ara-C opposite 8-oxo-dG, resulting in termination of DNA synthesis. Overall, these data suggest that incorporation of Ara-C opposite unrepaired 8-oxo-dG may be the fundamental mechanism conferring selective toxicity and therapeutic effectiveness in OGG1-deficient AML cells. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	AML therapy; DNA polymerase delta; DNA repair; DNA replication; Fragile site
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180286
作者单位	Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States
推荐引用方式 GB/T 7714	Owen N.,Minko I.G.,Moellmer S.A.,et al. Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells[J],2021,118(11).
APA	Owen N.,Minko I.G.,Moellmer S.A.,Cammann S.K.,Lloyd R.S.,&Amanda K. McCullough.(2021).Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells.Proceedings of the National Academy of Sciences of the United States of America,118(11).
MLA	Owen N.,et al."Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells".Proceedings of the National Academy of Sciences of the United States of America 118.11(2021).