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Enhanced cytarabine-induced killing in OGG1-deficient acute myeloid leukemia cells.

Authors :
Owen N
Minko IG
Moellmer SA
Cammann SK
Lloyd RS
McCullough AK
Source :
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2021 Mar 16; Vol. 118 (11).
Publication Year :
2021

Abstract

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 CBFB-MYH11 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.<br />Competing Interests: The authors declare no competing interest.

Details

Language :
English
ISSN :
1091-6490
Volume :
118
Issue :
11
Database :
MEDLINE
Journal :
Proceedings of the National Academy of Sciences of the United States of America
Publication Type :
Academic Journal
Accession number :
33836581
Full Text :
https://doi.org/10.1073/pnas.2016833118